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ESP: PubMed Auto Bibliography 31 Aug 2024 at 01:35 Created:
Telomeres
Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.
Created with PubMed® Query: telomere.q.txt NOT pmcbook NOT ispreviousversion
Citations The Papers (from PubMed®)
RevDate: 2024-08-28
Telomere biology disorders: from dyskeratosis congenita and beyond.
Postgraduate medical journal pii:7743326 [Epub ahead of print].
Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.
Additional Links: PMID-39197110
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@article {pmid39197110,
year = {2024},
author = {Roka, K and Solomou, E and Kattamis, A and Stiakaki, E},
title = {Telomere biology disorders: from dyskeratosis congenita and beyond.},
journal = {Postgraduate medical journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/postmj/qgae102},
pmid = {39197110},
issn = {1469-0756},
abstract = {Defective telomerase function or telomere maintenance causes genomic instability. Alterations in telomere length and/or attrition are the primary features of rare diseases known as telomere biology disorders or telomeropathies. Recent advances in the molecular basis of these disorders and cutting-edge methods assessing telomere length have increased our understanding of this topic. Multiorgan manifestations and different phenotypes have been reported even in carriers within the same family. In this context, apart from dyskeratosis congenita, disorders formerly considered idiopathic (i.e. pulmonary fibrosis, liver cirrhosis) frequently correlate with underlying defective telomere maintenance mechanisms. Moreover, these patients are prone to developing specific cancer types and exhibit exceptional sensitivity and toxicity in standard chemotherapy regimens. The current review describes the diverse spectrum of clinical manifestations of telomere biology disorders in pediatric and adult patients, their correlation with pathogenic variants, and considerations during their management to increase awareness and improve a multidisciplinary approach.},
}
RevDate: 2024-08-28
CmpDate: 2024-08-28
Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site.
Cells, 13(16): pii:cells13161361.
Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site.
Additional Links: PMID-39195250
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@article {pmid39195250,
year = {2024},
author = {Ghilain, C and Vidal-Cruchez, O and Joly, A and Debatisse, M and Gilson, E and Giraud-Panis, MJ},
title = {Innovative Tools for DNA Topology Probing in Human Cells Reveal a Build-Up of Positive Supercoils Following Replication Stress at Telomeres and at the FRA3B Fragile Site.},
journal = {Cells},
volume = {13},
number = {16},
pages = {},
doi = {10.3390/cells13161361},
pmid = {39195250},
issn = {2073-4409},
support = {TELOCHROM//Agence Nationale de la Recherche/ ; REPLITOP//French National Cancer Institute/ ; Equipe labellisée//Fondation ARC pour la Recherche sur le Cancer/ ; },
mesh = {Humans ; *Telomere/metabolism ; *DNA, Superhelical/metabolism ; *DNA Replication ; Chromosome Fragile Sites ; Telomeric Repeat Binding Protein 2/metabolism/genetics ; Nucleic Acid Conformation ; DNA/metabolism ; DNA Topoisomerases, Type II/metabolism ; },
abstract = {Linear unconstrained DNA cannot harbor supercoils since these supercoils can diffuse and be eliminated by free rotation of the DNA strands at the end of the molecule. Mammalian telomeres, despite constituting the ends of linear chromosomes, can hold supercoils and be subjected to topological stress. While negative supercoiling was previously observed, thus proving the existence of telomeric topological constraints, positive supercoils were never probed due to the lack of an appropriate tool. Indeed, the few tools available currently could only investigate unwound (Trioxsalen) or overwound (GapR) DNA topology (variations in twist) but not the variations in writhe (supercoils and plectonemes). To address this question, we have designed innovative tools aimed at analyzing both positive and negative DNA writhe in cells. Using them, we could observe the build-up of positive supercoils following replication stress and inhibition of Topoisomerase 2 on telomeres. TRF2 depletion caused both telomere relaxation and an increase in positive supercoils while the inhibition of Histone Deacetylase I and II by TSA only caused telomere relaxation. Moving outside telomeres, we also observed a build-up of positive supercoils on the FRA3B fragile site following replication stress, suggesting a topological model of DNA fragility for this site.},
}
MeSH Terms:
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Humans
*Telomere/metabolism
*DNA, Superhelical/metabolism
*DNA Replication
Chromosome Fragile Sites
Telomeric Repeat Binding Protein 2/metabolism/genetics
Nucleic Acid Conformation
DNA/metabolism
DNA Topoisomerases, Type II/metabolism
RevDate: 2024-08-28
Children exposed to salt-dust emission from Urmia Lake have short telomere length: a case-control pilot study.
International journal of environmental health research [Epub ahead of print].
This study aimed to measure telomere length in healthy children living next to Urmia Lake, Iran, which is exposed to salt dust from a drying lakebed. In this case-control pilot study, we recruited 39 sex- and age-matched healthy children from two different geographic regions to study the relative telomere lengths using qPCR. We categorized the study samples into high-impact and low-impact areas based on wind direction, aerosol particle level, and distance from the lake. Our main results revealed that children living in high-impact areas have shorter telomeres than those living in low-impact areas. Furthermore, according to our statistical model, parental age significantly affected telomere length in children, but inversely. When the father's age impact was positive, the mother had a negative effect. Based on our results, to prevent Urmia Lake from dying out completely, national and international organizations should implement comprehensive visions and strategies for its restoration.
Additional Links: PMID-39192622
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@article {pmid39192622,
year = {2024},
author = {Aali, R and Asli Gharehbagh, H and Gholampour, A and Sorooshian, A and Panahi, Y},
title = {Children exposed to salt-dust emission from Urmia Lake have short telomere length: a case-control pilot study.},
journal = {International journal of environmental health research},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/09603123.2024.2394136},
pmid = {39192622},
issn = {1369-1619},
abstract = {This study aimed to measure telomere length in healthy children living next to Urmia Lake, Iran, which is exposed to salt dust from a drying lakebed. In this case-control pilot study, we recruited 39 sex- and age-matched healthy children from two different geographic regions to study the relative telomere lengths using qPCR. We categorized the study samples into high-impact and low-impact areas based on wind direction, aerosol particle level, and distance from the lake. Our main results revealed that children living in high-impact areas have shorter telomeres than those living in low-impact areas. Furthermore, according to our statistical model, parental age significantly affected telomere length in children, but inversely. When the father's age impact was positive, the mother had a negative effect. Based on our results, to prevent Urmia Lake from dying out completely, national and international organizations should implement comprehensive visions and strategies for its restoration.},
}
RevDate: 2024-08-27
Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers.
Clinical epigenetics, 16(1):120.
BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.
METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).
RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).
CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.
Additional Links: PMID-39192284
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@article {pmid39192284,
year = {2024},
author = {Zhuang, X and Chen, P and Yang, R and Man, X and Wang, R and Shi, Y},
title = {Mendelian randomization analysis reveals the combined effects of epigenetics and telomere biology in hematologic cancers.},
journal = {Clinical epigenetics},
volume = {16},
number = {1},
pages = {120},
pmid = {39192284},
issn = {1868-7083},
support = {Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; Y20240077//the Public Welfare Science and Technology Project of Wenzhou/ ; No. LQ19H080002//Natural Science Foundation of Zhejiang Province/ ; },
abstract = {BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.
METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran's Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).
RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).
CONCLUSION: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.},
}
RevDate: 2024-08-27
Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences.
Nature genetics [Epub ahead of print].
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
Additional Links: PMID-39192095
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@article {pmid39192095,
year = {2024},
author = {Burren, OS and Dhindsa, RS and Deevi, SVV and Wen, S and Nag, A and Mitchell, J and Hu, F and Loesch, DP and Smith, KR and Razdan, N and Olsson, H and Platt, A and Vitsios, D and Wu, Q and , and Codd, V and Nelson, CP and Samani, NJ and March, RE and Wasilewski, S and Carss, K and Fabre, M and Wang, Q and Pangalos, MN and Petrovski, S},
title = {Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {39192095},
issn = {1546-1718},
support = {MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; MR/M012816/1//RCUK | Medical Research Council (MRC)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; BRC-1215-20010//DH | National Institute for Health Research (NIHR)/ ; MR/M012816/1//British Heart Foundation (BHF)/ ; },
abstract = {Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.},
}
RevDate: 2024-08-27
CmpDate: 2024-08-27
COVID-19 increases mortality in hemodialysis patients: exploring links with inflammation and telomere attrition.
Molecular biology reports, 51(1):938.
BACKGROUND AND OBJECTIVE: An increased risk of mortality and hospitalization was consistently demonstrated in hemodialysis (HD) patients affected by pandemic coronavirus infection (COVID-19). In this study, we analyzed parameters that may impact mortality in COVID-19 HD patients, including neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP), COVID-19 disease status and telomere length in peripheral blood cells (TL).
MATERIALS AND METHODS: A total of 130 chronic hemodialysis patients were enrolled and followed up for 18 months. Patients were categorized into groups based on their COVID-19 disease history and subsequent data about their survival status at the end of the study. Routine laboratory parameters were assessed using standard automated methods and TL was determined using the modified Cawthon method. Survival predictors were analyzed using Kaplan-Meier analysis.
RESULTS: Deceased patients (30%) were older with higher body mass index (BMI), higher levels of LDH, NLR index, CRP and lower TL and lymphocytes count compared to survivors. Kaplan-Meier survival analysis showed six parameters were significant mortality predictors in the following order of significance: COVID-19 history, 2-years cardiovascular mortality risk score, NLR, TL, CRP, LDH. Using binary logistic regression analysis Summary risk score, a combination of these six parameters revealed as the best predictor of patient's survival in this group of parameters (log rank 25.4, p < 0.001).
CONCLUSION: Compared to the general population, the mortality rate among HD patients persists at a higher level despite advancements in HD technology and patient care. The situation has been exacerbated by COVID-19, by significant increase in mortality rate among these patients.
Additional Links: PMID-39190187
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@article {pmid39190187,
year = {2024},
author = {Milosevic, T and Naumovic, R and Sopic, M and Vekic, J and Guzonjic, A and Pesic, S and Miljkovic-Trailovic, M and Kotur-Stevuljevic, J},
title = {COVID-19 increases mortality in hemodialysis patients: exploring links with inflammation and telomere attrition.},
journal = {Molecular biology reports},
volume = {51},
number = {1},
pages = {938},
pmid = {39190187},
issn = {1573-4978},
support = {451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; 451-03-47/2023 01/ 200161//Ministry of Education, Science, and Technological Development, Republic of Serbia, through Grant Agreement with the University of Belgrade-Faculty of Pharmacy/ ; },
mesh = {Humans ; *COVID-19/mortality/virology ; Male ; Female ; *Renal Dialysis ; Middle Aged ; Aged ; *C-Reactive Protein/metabolism ; *Inflammation ; Lymphocytes/metabolism ; Neutrophils/metabolism ; Telomere/genetics/metabolism ; SARS-CoV-2 ; L-Lactate Dehydrogenase/blood ; Kaplan-Meier Estimate ; Kidney Failure, Chronic/therapy/mortality/blood ; },
abstract = {BACKGROUND AND OBJECTIVE: An increased risk of mortality and hospitalization was consistently demonstrated in hemodialysis (HD) patients affected by pandemic coronavirus infection (COVID-19). In this study, we analyzed parameters that may impact mortality in COVID-19 HD patients, including neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP), COVID-19 disease status and telomere length in peripheral blood cells (TL).
MATERIALS AND METHODS: A total of 130 chronic hemodialysis patients were enrolled and followed up for 18 months. Patients were categorized into groups based on their COVID-19 disease history and subsequent data about their survival status at the end of the study. Routine laboratory parameters were assessed using standard automated methods and TL was determined using the modified Cawthon method. Survival predictors were analyzed using Kaplan-Meier analysis.
RESULTS: Deceased patients (30%) were older with higher body mass index (BMI), higher levels of LDH, NLR index, CRP and lower TL and lymphocytes count compared to survivors. Kaplan-Meier survival analysis showed six parameters were significant mortality predictors in the following order of significance: COVID-19 history, 2-years cardiovascular mortality risk score, NLR, TL, CRP, LDH. Using binary logistic regression analysis Summary risk score, a combination of these six parameters revealed as the best predictor of patient's survival in this group of parameters (log rank 25.4, p < 0.001).
CONCLUSION: Compared to the general population, the mortality rate among HD patients persists at a higher level despite advancements in HD technology and patient care. The situation has been exacerbated by COVID-19, by significant increase in mortality rate among these patients.},
}
MeSH Terms:
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Humans
*COVID-19/mortality/virology
Male
Female
*Renal Dialysis
Middle Aged
Aged
*C-Reactive Protein/metabolism
*Inflammation
Lymphocytes/metabolism
Neutrophils/metabolism
Telomere/genetics/metabolism
SARS-CoV-2
L-Lactate Dehydrogenase/blood
Kaplan-Meier Estimate
Kidney Failure, Chronic/therapy/mortality/blood
RevDate: 2024-08-27
The molecular mechanism for TERRA recruitment and annealing to telomeres.
Nucleic acids research pii:7742383 [Epub ahead of print].
Telomeric repeat containing RNA (TERRA) is a noncoding RNA that is transcribed from telomeres. Previous study showed that TERRA trans anneals by invading into the telomeric duplex to form an R-loop in mammalian cells. Here, we elucidate the molecular mechanism underlying TERRA recruitment and invasion into telomeres in the context of shelterin proteins, RAD51 and RNase H using single molecule (sm) assays. We demonstrate that TERRA trans annealing into telomeric DNA exhibits dynamic movement that is stabilized by TRF2. TERRA annealing to the telomeric duplex results in the formation of a stable triplex structure which differs from a conventional R-loop. We identified that the presence of a sub-telomeric DNA and a telomeric overhang in the form of a G-quadruplex significantly enhances TERRA annealing to telomeric duplex. We also demonstrate that RAD51-TERRA complex invades telomere duplex more efficiently than TERRA alone. Additionally, TRF2 increases TERRA affinity to telomeric duplex and protects it from RNase H digestion. In contrast, TRF1 represses TERRA annealing to telomeric duplex and fails to provide protection against RNase H digestion. Our findings provide an in-depth molecular mechanism underpinning TERRA recruitment and annealing to the telomere.
Additional Links: PMID-39189448
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@article {pmid39189448,
year = {2024},
author = {Wondimagegnhu, B and Ma, W and Paul, T and Liao, TW and Lee, CY and Sanford, S and Opresko, PL and Myong, S},
title = {The molecular mechanism for TERRA recruitment and annealing to telomeres.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae732},
pmid = {39189448},
issn = {1362-4962},
support = {F31CA268939/GF/NIH HHS/United States ; },
abstract = {Telomeric repeat containing RNA (TERRA) is a noncoding RNA that is transcribed from telomeres. Previous study showed that TERRA trans anneals by invading into the telomeric duplex to form an R-loop in mammalian cells. Here, we elucidate the molecular mechanism underlying TERRA recruitment and invasion into telomeres in the context of shelterin proteins, RAD51 and RNase H using single molecule (sm) assays. We demonstrate that TERRA trans annealing into telomeric DNA exhibits dynamic movement that is stabilized by TRF2. TERRA annealing to the telomeric duplex results in the formation of a stable triplex structure which differs from a conventional R-loop. We identified that the presence of a sub-telomeric DNA and a telomeric overhang in the form of a G-quadruplex significantly enhances TERRA annealing to telomeric duplex. We also demonstrate that RAD51-TERRA complex invades telomere duplex more efficiently than TERRA alone. Additionally, TRF2 increases TERRA affinity to telomeric duplex and protects it from RNase H digestion. In contrast, TRF1 represses TERRA annealing to telomeric duplex and fails to provide protection against RNase H digestion. Our findings provide an in-depth molecular mechanism underpinning TERRA recruitment and annealing to the telomere.},
}
RevDate: 2024-08-27
Association of hTERT expression, Her2Neu, estrogen receptors, progesterone receptors, with telomere length before and at the end of treatment in breast cancer patients.
Frontiers in medicine, 11:1450147.
BACKGROUND: Breast cancer shows significant clinical, morphologic, and molecular variation. Telomeres are nucleoprotein complexes composed of hexanucleotide repeat DNA sequence, TTAGGG, and numerous telomere-associated proteins. The maintenance of telomere length is carried out by a ribonucleoprotein called telomerase, which consists of two main components: a catalytic subunit called hTERT (human telomerase reverse transcriptase) and an RNA template called hTR (human telomerase RNA). The importance of evaluating hTERT expression lies in its potential therapeutic application, being an attractive target due to its almost non-existent expression in normal somatic cells. It is also expected that the anti-neoplastic effect would appear earlier in neoplastic cells with shorter telomeres. Additionally, a significant relationship has been observed between Her2-Neu overexpression and Her2-Neu positivity, which could suggest new combined therapies.The aim of this study was to detect the expression of hTERT, estrogen receptor (ER), progesterone receptor (PR), and HER2-Neu in neoplastic breast tissue embedded in paraffin before treatment and to investigate the relationship between them and with baseline and post-treatment telomere length, as well as with various clinicopathological parameters.
MATERIALS AND METHODS: A cross-sectional-correlational, 21 women diagnosed with breast cancer at the Oncology Service of the High Specialty Medical Unit No. 1 of Bajio of the Mexican Institute of Social Security. The study complies with the Helsinki Declaration and was approved by the Institutional Ethical Committee of the Mexican Institute of Social Security (R-2019-1001-127). A peripheral blood sample was obtained before oncological treatment and at the end of oncological treatment for the measurement of telomere length by extracting DNA from leukocytes, was performed by the quantitative polymerase chain reaction (PCR) method described by Cawthon. Tumor samples were collected from each patient at the oncology department for immunohistochemical determination of biomarker expression (ER, PR, Her2/neu) and hTERT.
RESULTS: Of the 21 cases included in the study, the median age was 57.57 years. Eighteen cases were classified as invasive ductal carcinoma NOS (85.71%), 10 were histologic grade 2 (47.61%), 16 cases were hormone receptor positive (76.19%), 7 were Her2Neu positive (33.33%), and only 2 cases were triple negative (9.52%). Positive hTERT expression was detected in 11 cases (52.38%) and was negative in the remaining cases. A significant association was identified between hTERT-positive cases and Her2-Neu positive cases (p = 0.04). Baseline and post-treatment telomere lengths showed a significant difference using the non-parametric Wilcoxon t-test (p = 0.002). In hTERT-positive cases, there was significant telomere shortening at the end of oncological treatment (6.14 ± 1.54 vs. 4.75 ± 1.96 Kb, p = 0.007).
CONCLUSION: Positive hTERT immunostaining cases were associated with poor prognostic factors, such as Her2-Neu overexpression and post-treatment telomere shortening. In the future, hTERT immunostaining could be used to select patients for therapies with antagonistic effects on hTERT, as well as in the selection of more appropriate chemotherapy regimens for patients who express it.
Additional Links: PMID-39188883
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@article {pmid39188883,
year = {2024},
author = {Murillo-Ortiz, BO and García-Corrales, K and Martínez-Garza, S and Romero-Vázquez, MJ and Agustín-Godínez, E and Escareño-Gómez, A and Silva-Guerrero, DG and Mendoza-Ramírez, S and Murguia-Perez, M},
title = {Association of hTERT expression, Her2Neu, estrogen receptors, progesterone receptors, with telomere length before and at the end of treatment in breast cancer patients.},
journal = {Frontiers in medicine},
volume = {11},
number = {},
pages = {1450147},
pmid = {39188883},
issn = {2296-858X},
abstract = {BACKGROUND: Breast cancer shows significant clinical, morphologic, and molecular variation. Telomeres are nucleoprotein complexes composed of hexanucleotide repeat DNA sequence, TTAGGG, and numerous telomere-associated proteins. The maintenance of telomere length is carried out by a ribonucleoprotein called telomerase, which consists of two main components: a catalytic subunit called hTERT (human telomerase reverse transcriptase) and an RNA template called hTR (human telomerase RNA). The importance of evaluating hTERT expression lies in its potential therapeutic application, being an attractive target due to its almost non-existent expression in normal somatic cells. It is also expected that the anti-neoplastic effect would appear earlier in neoplastic cells with shorter telomeres. Additionally, a significant relationship has been observed between Her2-Neu overexpression and Her2-Neu positivity, which could suggest new combined therapies.The aim of this study was to detect the expression of hTERT, estrogen receptor (ER), progesterone receptor (PR), and HER2-Neu in neoplastic breast tissue embedded in paraffin before treatment and to investigate the relationship between them and with baseline and post-treatment telomere length, as well as with various clinicopathological parameters.
MATERIALS AND METHODS: A cross-sectional-correlational, 21 women diagnosed with breast cancer at the Oncology Service of the High Specialty Medical Unit No. 1 of Bajio of the Mexican Institute of Social Security. The study complies with the Helsinki Declaration and was approved by the Institutional Ethical Committee of the Mexican Institute of Social Security (R-2019-1001-127). A peripheral blood sample was obtained before oncological treatment and at the end of oncological treatment for the measurement of telomere length by extracting DNA from leukocytes, was performed by the quantitative polymerase chain reaction (PCR) method described by Cawthon. Tumor samples were collected from each patient at the oncology department for immunohistochemical determination of biomarker expression (ER, PR, Her2/neu) and hTERT.
RESULTS: Of the 21 cases included in the study, the median age was 57.57 years. Eighteen cases were classified as invasive ductal carcinoma NOS (85.71%), 10 were histologic grade 2 (47.61%), 16 cases were hormone receptor positive (76.19%), 7 were Her2Neu positive (33.33%), and only 2 cases were triple negative (9.52%). Positive hTERT expression was detected in 11 cases (52.38%) and was negative in the remaining cases. A significant association was identified between hTERT-positive cases and Her2-Neu positive cases (p = 0.04). Baseline and post-treatment telomere lengths showed a significant difference using the non-parametric Wilcoxon t-test (p = 0.002). In hTERT-positive cases, there was significant telomere shortening at the end of oncological treatment (6.14 ± 1.54 vs. 4.75 ± 1.96 Kb, p = 0.007).
CONCLUSION: Positive hTERT immunostaining cases were associated with poor prognostic factors, such as Her2-Neu overexpression and post-treatment telomere shortening. In the future, hTERT immunostaining could be used to select patients for therapies with antagonistic effects on hTERT, as well as in the selection of more appropriate chemotherapy regimens for patients who express it.},
}
RevDate: 2024-08-27
Leukocyte Telomere Shortening in MASLD and All-cause/Cause-specific Mortality.
Clinical and molecular hepatology pii:cmh.2024.0691 [Epub ahead of print].
Additional Links: PMID-39188229
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@article {pmid39188229,
year = {2024},
author = {Kim, D and Danpanichkul, P and Wijarnpreecha, K and Cholankeril, G and Ahmed, A},
title = {Leukocyte Telomere Shortening in MASLD and All-cause/Cause-specific Mortality.},
journal = {Clinical and molecular hepatology},
volume = {},
number = {},
pages = {},
doi = {10.3350/cmh.2024.0691},
pmid = {39188229},
issn = {2287-285X},
}
RevDate: 2024-08-23
CmpDate: 2024-08-24
Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis.
Orphanet journal of rare diseases, 19(1):309.
BACKGROUND: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.
METHODS: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.
RESULTS: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.
CONCLUSION: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.
Additional Links: PMID-39180127
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Citation:
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@article {pmid39180127,
year = {2024},
author = {Song, Y and Xu, J and Geng, W and Yin, L and Wang, J and Zhao, J},
title = {Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis.},
journal = {Orphanet journal of rare diseases},
volume = {19},
number = {1},
pages = {309},
pmid = {39180127},
issn = {1750-1172},
support = {no. 19-1124-038//Shenyang Science and Technology Bureau, China/ ; },
mesh = {Humans ; *Telomerase/genetics ; *Mendelian Randomization Analysis ; *Cerebral Small Vessel Diseases/genetics ; *Polymorphism, Single Nucleotide/genetics ; Female ; *Leukocytes/metabolism ; Male ; Middle Aged ; Asian People/genetics ; Aged ; Telomere/genetics ; Genetic Predisposition to Disease ; Genotype ; China ; Risk Factors ; East Asian People ; },
abstract = {BACKGROUND: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.
METHODS: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.
RESULTS: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.
CONCLUSION: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.},
}
MeSH Terms:
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Humans
*Telomerase/genetics
*Mendelian Randomization Analysis
*Cerebral Small Vessel Diseases/genetics
*Polymorphism, Single Nucleotide/genetics
Female
*Leukocytes/metabolism
Male
Middle Aged
Asian People/genetics
Aged
Telomere/genetics
Genetic Predisposition to Disease
Genotype
China
Risk Factors
East Asian People
RevDate: 2024-08-23
Sex-specific modulating role of social support in the associations between oxidative stress, inflammation, and telomere length in older adults.
Journal of behavioral medicine [Epub ahead of print].
Telomere length, a biomarker of human aging, is related to adverse health outcomes. Growing evidence indicates that oxidative stress and inflammation contributes to telomere shortening, whereas social support may protect from telomere shortening. Despite sex differences in telomere length and social support, little is known about whether there are sex differences in the relationship between oxidative stress/inflammation and telomere length, and sex-specific moderating roles of social support in older adults. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, this study assessed whether the associations between oxidative stress/inflammation and telomere length vary with sex and explored social support as a moderator in these associations among 2289 older adults. Oxidative stress was measured based on serum Gamma-glutamyl transferase (GGT), and inflammation was measured based on C-reactive protein (CRP). After adjusting for the covariates, GGT was significantly associated with telomere length in females only (β = - 0.037, 95% CI = - 0.070, - 0.005), while CRP was associated with telomere length in males only (β = - 0.019, 95% CI = - 0.035, - 0.002). Moreover, high social support mitigated the negative association between GGT and telomere length, which was more evident in females. Furthermore, social support moderated the association between CRP and telomere length in males aged 70 and above. Our findings indicated that biological mechanisms related to telomere length may vary with sex, while social support plays a sex-specific moderating role.
Additional Links: PMID-39179728
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Citation:
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@article {pmid39179728,
year = {2024},
author = {Jin, Z and Liu, X and Guo, H and Chen, S and Zhu, X and Pan, S and Wu, Y},
title = {Sex-specific modulating role of social support in the associations between oxidative stress, inflammation, and telomere length in older adults.},
journal = {Journal of behavioral medicine},
volume = {},
number = {},
pages = {},
pmid = {39179728},
issn = {1573-3521},
support = {81971019//National Natural Science Foundation of China/ ; 82271482//National Natural Science Foundation of China/ ; },
abstract = {Telomere length, a biomarker of human aging, is related to adverse health outcomes. Growing evidence indicates that oxidative stress and inflammation contributes to telomere shortening, whereas social support may protect from telomere shortening. Despite sex differences in telomere length and social support, little is known about whether there are sex differences in the relationship between oxidative stress/inflammation and telomere length, and sex-specific moderating roles of social support in older adults. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, this study assessed whether the associations between oxidative stress/inflammation and telomere length vary with sex and explored social support as a moderator in these associations among 2289 older adults. Oxidative stress was measured based on serum Gamma-glutamyl transferase (GGT), and inflammation was measured based on C-reactive protein (CRP). After adjusting for the covariates, GGT was significantly associated with telomere length in females only (β = - 0.037, 95% CI = - 0.070, - 0.005), while CRP was associated with telomere length in males only (β = - 0.019, 95% CI = - 0.035, - 0.002). Moreover, high social support mitigated the negative association between GGT and telomere length, which was more evident in females. Furthermore, social support moderated the association between CRP and telomere length in males aged 70 and above. Our findings indicated that biological mechanisms related to telomere length may vary with sex, while social support plays a sex-specific moderating role.},
}
RevDate: 2024-08-23
Leukocyte Telomere Length and Mitochondrial DNA Copy Number in Treatment-Resistant Depression and Response to Electroconvulsive Therapy: A Pilot Longitudinal Study.
The journal of ECT pii:00124509-990000000-00206 [Epub ahead of print].
OBJECTIVES: In this study, we investigated if changes in leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-cn), 2 markers of cellular aging, are associated with treatment-resistant depression (TRD) and with response to electroconvulsive therapy (ECT).
METHODS: LTL and mtDNA-cn were measured in 31 TRD patients before (T0), 1 week (T1), and 4 weeks (T2) after the ECT course, as well as in a sample of 65 healthy controls.
RESULTS: TRD patients had significantly shorter LTL and higher mtDNA-cn compared with healthy controls at baseline. In the TRD sample, LTL was inversely correlated with Montgomery-Åsberg Depression Rating Scale scores at baseline. Baseline levels of LTL or mtDNA-cn were not correlated with response to ECT. Similarly, changes in LTL or mtDNA-cn were not associated with response to ECT either when considered as a dichotomous trait (responders vs nonresponders) or as a percentage change in symptoms improvements.
CONCLUSIONS: Ours is the first longitudinal study exploring the role of LTL and mtDNA-cn in response to ECT. Findings of this pilot investigation suggest that LTL and mtDNA-cn may constitute disease biomarkers for TRD but are not involved in response to ECT.
Additional Links: PMID-39178054
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@article {pmid39178054,
year = {2024},
author = {Squassina, A and Pisanu, C and Menesello, V and Meloni, A and Congiu, D and Manchia, M and Paribello, P and Abate, M and Bortolomasi, M and Baune, BT and Gennarelli, M and Minelli, A},
title = {Leukocyte Telomere Length and Mitochondrial DNA Copy Number in Treatment-Resistant Depression and Response to Electroconvulsive Therapy: A Pilot Longitudinal Study.},
journal = {The journal of ECT},
volume = {},
number = {},
pages = {},
doi = {10.1097/YCT.0000000000001060},
pmid = {39178054},
issn = {1533-4112},
abstract = {OBJECTIVES: In this study, we investigated if changes in leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-cn), 2 markers of cellular aging, are associated with treatment-resistant depression (TRD) and with response to electroconvulsive therapy (ECT).
METHODS: LTL and mtDNA-cn were measured in 31 TRD patients before (T0), 1 week (T1), and 4 weeks (T2) after the ECT course, as well as in a sample of 65 healthy controls.
RESULTS: TRD patients had significantly shorter LTL and higher mtDNA-cn compared with healthy controls at baseline. In the TRD sample, LTL was inversely correlated with Montgomery-Åsberg Depression Rating Scale scores at baseline. Baseline levels of LTL or mtDNA-cn were not correlated with response to ECT. Similarly, changes in LTL or mtDNA-cn were not associated with response to ECT either when considered as a dichotomous trait (responders vs nonresponders) or as a percentage change in symptoms improvements.
CONCLUSIONS: Ours is the first longitudinal study exploring the role of LTL and mtDNA-cn in response to ECT. Findings of this pilot investigation suggest that LTL and mtDNA-cn may constitute disease biomarkers for TRD but are not involved in response to ECT.},
}
RevDate: 2024-08-23
Investigation of G-Quadruplex DNA-Mediated Charge Transport for Exploring DNA Oxidative Damage in Telomeres.
Langmuir : the ACS journal of surfaces and colloids [Epub ahead of print].
The human telomeric DNA 3' single-stranded overhang comprises tandem repeats of the sequence d(TTAGGG), which can fold into the stable secondary structure G-quadruplex (G4) and is susceptible to oxidative damage due to the enrichment of G bases. 8-Oxoguanine (8-oxoG) formed in telomeric DNA destabilizes G4 secondary structures and then inhibits telomere functions such as the binding of G4 proteins and the regulation of the length of telomeres. In this work, we developed a G4-DNA self-assembled monolayer electrochemical sensing interface using copper-free click chemistry based on the reaction of dibenzocyclooctyl with azide, resulting in a high yield of DNA tethers with order and homogeneity surfaces, that is more suitable for G-quadruplex DNA charge transport (CT) research. At high DNA coverage density surfaces, G-quadruplex DNA is 4 times more conductive than double-stranded DNA owing to the well-stacked aromatic rings of G-quartets acting as good charge transfer channels. The effect of telomeric oxidative damage on G-quadruplex-mediated CT is investigated. The accommodation of 8-oxoG at G sites originally in the syn or anti conformation around the glycosyl bond in the nonsubstituted hTel G-quadruplex causes structural perturbation and a conformational shift, which disrupts the π-stack, affecting the charge transfer and attenuating the electrochemical signal. The current intensity was found to correlate with the amount of 8-oxodG, and the detection limit was estimated to be approximately one lesion in 286 DNA bases, which can be converted into 64.7 fmol on the basis of the total surface DNA coverage. The improved G4-DNA order and homogeneity sensing interface represent a major step forward in this regard, providing a reliable and controlled electrochemical platform for the accurate measurement and diagnosis of G4-DNA oxidative damage.
Additional Links: PMID-39177475
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PubMed:
Citation:
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@article {pmid39177475,
year = {2024},
author = {He, Z and Wu, J and Li, W and Du, Y and Lu, L},
title = {Investigation of G-Quadruplex DNA-Mediated Charge Transport for Exploring DNA Oxidative Damage in Telomeres.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.4c01604},
pmid = {39177475},
issn = {1520-5827},
abstract = {The human telomeric DNA 3' single-stranded overhang comprises tandem repeats of the sequence d(TTAGGG), which can fold into the stable secondary structure G-quadruplex (G4) and is susceptible to oxidative damage due to the enrichment of G bases. 8-Oxoguanine (8-oxoG) formed in telomeric DNA destabilizes G4 secondary structures and then inhibits telomere functions such as the binding of G4 proteins and the regulation of the length of telomeres. In this work, we developed a G4-DNA self-assembled monolayer electrochemical sensing interface using copper-free click chemistry based on the reaction of dibenzocyclooctyl with azide, resulting in a high yield of DNA tethers with order and homogeneity surfaces, that is more suitable for G-quadruplex DNA charge transport (CT) research. At high DNA coverage density surfaces, G-quadruplex DNA is 4 times more conductive than double-stranded DNA owing to the well-stacked aromatic rings of G-quartets acting as good charge transfer channels. The effect of telomeric oxidative damage on G-quadruplex-mediated CT is investigated. The accommodation of 8-oxoG at G sites originally in the syn or anti conformation around the glycosyl bond in the nonsubstituted hTel G-quadruplex causes structural perturbation and a conformational shift, which disrupts the π-stack, affecting the charge transfer and attenuating the electrochemical signal. The current intensity was found to correlate with the amount of 8-oxodG, and the detection limit was estimated to be approximately one lesion in 286 DNA bases, which can be converted into 64.7 fmol on the basis of the total surface DNA coverage. The improved G4-DNA order and homogeneity sensing interface represent a major step forward in this regard, providing a reliable and controlled electrochemical platform for the accurate measurement and diagnosis of G4-DNA oxidative damage.},
}
RevDate: 2024-08-22
X-chromosome inactivation pattern and telomere length in recurrent pregnancy loss.
Reproductive biology, 24(4):100933 pii:S1642-431X(24)00079-2 [Epub ahead of print].
Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.
Additional Links: PMID-39173315
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PubMed:
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@article {pmid39173315,
year = {2024},
author = {Vaz, D and Vasconcelos, S and Caniçais, C and Costa, B and Ramalho, C and Marques, J and Dória, S},
title = {X-chromosome inactivation pattern and telomere length in recurrent pregnancy loss.},
journal = {Reproductive biology},
volume = {24},
number = {4},
pages = {100933},
doi = {10.1016/j.repbio.2024.100933},
pmid = {39173315},
issn = {2300-732X},
abstract = {Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.},
}
RevDate: 2024-08-22
Micronutrient intake and telomere length: findings from the UK Biobank.
European journal of nutrition [Epub ahead of print].
PURPOSE: To investigate whether micronutrient intake from food as well as the regular uptake of specific vitamins and/or minerals are associated with leucocyte telomere length (LTL).
METHODS: This is a cross-sectional study using data from 422,693 UK Biobank participants aged from 40 to 69 years old, during 2006-2010. LTL was measured as the ratio of telomere repeat number to a single-copy gene and was loge-transformed and z-standardized (z-LTL). Information concerning supplement use was collected at baseline through the touchscreen assessment, while micronutrient intake from food were self-reported through multiple web-based 24 h recall diaries. The association between micronutrient intake or supplement use and z-LTL was assessed using multivariable linear regression models adjusting for demographic, lifestyle and clinical characteristics.
RESULTS: About 50% (n = 131,810) of the participants, with complete data on all covariates, self-reported regular supplement intake. Whilst overall supplement intake was not associated with z-LTL, trends toward shorter z-LTL with regular vitamin B (-0.019 (95% CI: -0.041; 0.002)) and vitamin B9 (-0.027 (-0.054; 0.000)) supplement intake were observed. z-LTL was associated with food intake of pantothenic acid (-0.020 (-0.033; -0.007)), vitamin B6 (-0.015 (-0.027; -0.003)), biotin (0.010 (0.002; 0.018)) and folate (0.016 (0.003; 0.030)). Associations of z-LTL with these micronutrients were differentiated according to supplement intake.
CONCLUSION: Negative associations equivalent to a year or less of age-related change in LTL between micronutrient intake and LTL were observed. Due to this small effect, the clinical importance of the associations and any relevance to the effects of vitamin and micronutrient intake toward chronic disease prevention remains uncertain.
Additional Links: PMID-39174689
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@article {pmid39174689,
year = {2024},
author = {Spinou, M and Naska, A and Nelson, CP and Codd, V and Samani, NJ and Bountziouka, V},
title = {Micronutrient intake and telomere length: findings from the UK Biobank.},
journal = {European journal of nutrition},
volume = {},
number = {},
pages = {},
pmid = {39174689},
issn = {1436-6215},
support = {MR/M012816/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {PURPOSE: To investigate whether micronutrient intake from food as well as the regular uptake of specific vitamins and/or minerals are associated with leucocyte telomere length (LTL).
METHODS: This is a cross-sectional study using data from 422,693 UK Biobank participants aged from 40 to 69 years old, during 2006-2010. LTL was measured as the ratio of telomere repeat number to a single-copy gene and was loge-transformed and z-standardized (z-LTL). Information concerning supplement use was collected at baseline through the touchscreen assessment, while micronutrient intake from food were self-reported through multiple web-based 24 h recall diaries. The association between micronutrient intake or supplement use and z-LTL was assessed using multivariable linear regression models adjusting for demographic, lifestyle and clinical characteristics.
RESULTS: About 50% (n = 131,810) of the participants, with complete data on all covariates, self-reported regular supplement intake. Whilst overall supplement intake was not associated with z-LTL, trends toward shorter z-LTL with regular vitamin B (-0.019 (95% CI: -0.041; 0.002)) and vitamin B9 (-0.027 (-0.054; 0.000)) supplement intake were observed. z-LTL was associated with food intake of pantothenic acid (-0.020 (-0.033; -0.007)), vitamin B6 (-0.015 (-0.027; -0.003)), biotin (0.010 (0.002; 0.018)) and folate (0.016 (0.003; 0.030)). Associations of z-LTL with these micronutrients were differentiated according to supplement intake.
CONCLUSION: Negative associations equivalent to a year or less of age-related change in LTL between micronutrient intake and LTL were observed. Due to this small effect, the clinical importance of the associations and any relevance to the effects of vitamin and micronutrient intake toward chronic disease prevention remains uncertain.},
}
RevDate: 2024-08-22
DNA damage (8-OHdG) and telomere length in captive Psittacidae birds with different longevity.
Frontiers in veterinary science, 11:1430861.
Aging is a complex process influenced by internal and external factors. Oxidative stress damages DNA, leading to 8-hydroxy-2' deoxyguanosine formation (8-OHdG). Telomere shortening is considered a biomarker of aging and oxidative stress may enhance its attrition. The ability to manage and repair oxidative stress varies among species and life histories. Avian species, such as Psittacidae birds, exhibit exceptional lifespans despite their physiological characteristics that might suggest otherwise. This study investigates 8-OHdG levels in serum samples from long- and short-lived birds of the order Psittaciformes, examining their relationship with telomere length and antioxidant capacity based on lifespan strategies. Among 43 individuals analyzed 26 belonged to the "long-lived species" group and 17 belonged to the "short-lived species" one. Relative telomere length (rTL) was measured in DNA isolated from whole blood by qPCR, and oxidative stress markers, such as Total Antioxidant Capacity (TAC) and 8-OHdG, were determined by spectrophotometry in serum samples. Long-lived birds had longer rTL than short-lived ones [1.308 ± 0.11 vs. 0.565 ± 0.13, (p < 0.001)]. On the contrary, short-lived birds showed more DNA damage than their counterparts [3.847 ± 0.351 vs. 2.012 ± 0.308, respectively, (p < 0.001)]. Old birds had shorter rTL than young ones, for both longevity groups (p < 0.001). Although no correlation was found between 8-OHdG levels and age, nor 8-OHdG and telomere length, long-lived birds exhibited 75.42-unit increased TAC levels when increased 8-OHdG concentrations (p = 0.046). These findings highlight distinct patterns of telomere length and oxidative stress influenced by lifespan strategies among avian longevity groups.
Additional Links: PMID-39170634
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@article {pmid39170634,
year = {2024},
author = {Domínguez-de-Barros, A and Sifaoui, I and Dorta-Guerra, R and Lorenzo-Morales, J and Castro-Fuentes, R and Córdoba-Lanús, E},
title = {DNA damage (8-OHdG) and telomere length in captive Psittacidae birds with different longevity.},
journal = {Frontiers in veterinary science},
volume = {11},
number = {},
pages = {1430861},
pmid = {39170634},
issn = {2297-1769},
abstract = {Aging is a complex process influenced by internal and external factors. Oxidative stress damages DNA, leading to 8-hydroxy-2' deoxyguanosine formation (8-OHdG). Telomere shortening is considered a biomarker of aging and oxidative stress may enhance its attrition. The ability to manage and repair oxidative stress varies among species and life histories. Avian species, such as Psittacidae birds, exhibit exceptional lifespans despite their physiological characteristics that might suggest otherwise. This study investigates 8-OHdG levels in serum samples from long- and short-lived birds of the order Psittaciformes, examining their relationship with telomere length and antioxidant capacity based on lifespan strategies. Among 43 individuals analyzed 26 belonged to the "long-lived species" group and 17 belonged to the "short-lived species" one. Relative telomere length (rTL) was measured in DNA isolated from whole blood by qPCR, and oxidative stress markers, such as Total Antioxidant Capacity (TAC) and 8-OHdG, were determined by spectrophotometry in serum samples. Long-lived birds had longer rTL than short-lived ones [1.308 ± 0.11 vs. 0.565 ± 0.13, (p < 0.001)]. On the contrary, short-lived birds showed more DNA damage than their counterparts [3.847 ± 0.351 vs. 2.012 ± 0.308, respectively, (p < 0.001)]. Old birds had shorter rTL than young ones, for both longevity groups (p < 0.001). Although no correlation was found between 8-OHdG levels and age, nor 8-OHdG and telomere length, long-lived birds exhibited 75.42-unit increased TAC levels when increased 8-OHdG concentrations (p = 0.046). These findings highlight distinct patterns of telomere length and oxidative stress influenced by lifespan strategies among avian longevity groups.},
}
RevDate: 2024-08-20
CmpDate: 2024-08-20
RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.
Nature communications, 15(1):7138.
Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.
Additional Links: PMID-39164231
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@article {pmid39164231,
year = {2024},
author = {Ghosh, S and Nguyen, MT and Choi, HE and Stahl, M and Kühn, AL and Van der Auwera, S and Grabe, HJ and Völzke, H and Homuth, G and Myers, SA and Hogaboam, CM and Noth, I and Martinez, FJ and Petsko, GA and Glimcher, LH},
title = {RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {7138},
pmid = {39164231},
issn = {2041-1723},
mesh = {Humans ; *Idiopathic Pulmonary Fibrosis/genetics/metabolism/pathology ; *Telomere Shortening ; *Telomerase/metabolism/genetics ; *Nuclear Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; Fibroblasts/metabolism ; Myelodysplastic Syndromes/genetics/metabolism ; Telomere/metabolism/genetics ; Gene Expression Regulation ; Lung/metabolism/pathology ; },
abstract = {Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.},
}
MeSH Terms:
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Humans
*Idiopathic Pulmonary Fibrosis/genetics/metabolism/pathology
*Telomere Shortening
*Telomerase/metabolism/genetics
*Nuclear Proteins/metabolism/genetics
*Cell Cycle Proteins/metabolism/genetics
Fibroblasts/metabolism
Myelodysplastic Syndromes/genetics/metabolism
Telomere/metabolism/genetics
Gene Expression Regulation
Lung/metabolism/pathology
RevDate: 2024-08-19
DNA methylation-estimated phenotypes, telomere length and risk of ischemic stroke: epigenetic age acceleration of screening and a Mendelian randomization study.
Aging, 16: pii:206072 [Epub ahead of print].
BACKGROUND: Aging is a complex biological process that may be accelerated in certain pathological conditions. DNA methylation age (DNAmAge) has emerged as a biomarker for biological age, which can differ from chronological age. This research peels back the layers of the relationship between fast-forward aging and ischemic stroke, poking and prodding the potential two-way causal influences between stroke and biological aging indicators.
METHODS: We analyzed a cohort of ischemic stroke patients, comparing DNAmAge with chronological age to measure age acceleration. We assessed variations in age acceleration among stroke subtypes and between sexes. Using Mendelian randomization, we examined the causal links between stroke, aging biomarkers like telomere length, and age acceleration's effect on stroke risk.
RESULTS: Our investigation reveals a pronounced association between ischemic stroke and age acceleration, most notably in patients with cardioembolic strokes, who exhibited a striking median difference of 9 years between DNAmAge and chronological age. Furthermore, age acceleration differed significantly across stroke subtypes and was higher in women than in men. In terms of causality, MR analysis indicated a modest negative effect of stroke on telomere length, but no causal effect of age phenotypes on stroke or its subtypes. However, some indication of a potential causal effect of ischemic stroke on PhenoAge acceleration was observed.
CONCLUSION: The study provides insight into the relationship between DNAmAge and ischemic stroke, particularly cardioembolic stroke, and suggests possible gender differences. These insights carry profound clinical significance and set stage for future investigations into the entwined pathways of stroke and accelerated aging.
Additional Links: PMID-39159130
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@article {pmid39159130,
year = {2024},
author = {Maimaiti, A and Ma, J and Hao, C and Han, D and Wang, Y and Wang, Z and Abudusalamu, R},
title = {DNA methylation-estimated phenotypes, telomere length and risk of ischemic stroke: epigenetic age acceleration of screening and a Mendelian randomization study.},
journal = {Aging},
volume = {16},
number = {},
pages = {},
doi = {10.18632/aging.206072},
pmid = {39159130},
issn = {1945-4589},
abstract = {BACKGROUND: Aging is a complex biological process that may be accelerated in certain pathological conditions. DNA methylation age (DNAmAge) has emerged as a biomarker for biological age, which can differ from chronological age. This research peels back the layers of the relationship between fast-forward aging and ischemic stroke, poking and prodding the potential two-way causal influences between stroke and biological aging indicators.
METHODS: We analyzed a cohort of ischemic stroke patients, comparing DNAmAge with chronological age to measure age acceleration. We assessed variations in age acceleration among stroke subtypes and between sexes. Using Mendelian randomization, we examined the causal links between stroke, aging biomarkers like telomere length, and age acceleration's effect on stroke risk.
RESULTS: Our investigation reveals a pronounced association between ischemic stroke and age acceleration, most notably in patients with cardioembolic strokes, who exhibited a striking median difference of 9 years between DNAmAge and chronological age. Furthermore, age acceleration differed significantly across stroke subtypes and was higher in women than in men. In terms of causality, MR analysis indicated a modest negative effect of stroke on telomere length, but no causal effect of age phenotypes on stroke or its subtypes. However, some indication of a potential causal effect of ischemic stroke on PhenoAge acceleration was observed.
CONCLUSION: The study provides insight into the relationship between DNAmAge and ischemic stroke, particularly cardioembolic stroke, and suggests possible gender differences. These insights carry profound clinical significance and set stage for future investigations into the entwined pathways of stroke and accelerated aging.},
}
RevDate: 2024-08-17
Shortening of telomere length may be associated with inflammatory cytokine levels in patients with bipolar disorder.
Journal of affective disorders pii:S0165-0327(24)01302-8 [Epub ahead of print].
BACKGROUND: Bipolar disorder (BD) is hypothesized to be associated with accelerated biological aging. Telomere length (TL) is a biomarker of aging, and although TL decreases with each cell division, the rate of telomere shortening may be affected by inflammation. We aimed to investigate whether TL is decreased in BD patients and to determine the association between TL and inflammatory markers in such patients.
METHODS: 137 BD patients and 118 healthy controls (HCs) were recruited. Leukocyte TL and plasma levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, IL-10, transforming growth factor (TGF)-β1], C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were assessed.
RESULTS: TL did not differ significantly between the BD patients and HCs after adjustment for potential confounding factors (P = 0.79). TL was significantly negatively associated with age (β = -0.006, P < 0.001). In addition, log TNF-α levels were significantly negatively associated with TL (P = 0.009), in both the BD patients (P = 0.02) and HCs (P = 0.05).
CONCLUSION: We found a significant association between TNF-α levels and TL shortening in both BD patients and HCs. However, BD patients did not display increased TL shortening relative to HCs. Studies that involve larger sample sizes and control for the heterogeneity of BD participants will be needed.
Additional Links: PMID-39153550
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@article {pmid39153550,
year = {2024},
author = {Wang, SM and Chang, HH and Chang, YH and Tsai, TY and Chen, PS and Lu, RB and Wang, TY},
title = {Shortening of telomere length may be associated with inflammatory cytokine levels in patients with bipolar disorder.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jad.2024.08.084},
pmid = {39153550},
issn = {1573-2517},
abstract = {BACKGROUND: Bipolar disorder (BD) is hypothesized to be associated with accelerated biological aging. Telomere length (TL) is a biomarker of aging, and although TL decreases with each cell division, the rate of telomere shortening may be affected by inflammation. We aimed to investigate whether TL is decreased in BD patients and to determine the association between TL and inflammatory markers in such patients.
METHODS: 137 BD patients and 118 healthy controls (HCs) were recruited. Leukocyte TL and plasma levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, IL-10, transforming growth factor (TGF)-β1], C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were assessed.
RESULTS: TL did not differ significantly between the BD patients and HCs after adjustment for potential confounding factors (P = 0.79). TL was significantly negatively associated with age (β = -0.006, P < 0.001). In addition, log TNF-α levels were significantly negatively associated with TL (P = 0.009), in both the BD patients (P = 0.02) and HCs (P = 0.05).
CONCLUSION: We found a significant association between TNF-α levels and TL shortening in both BD patients and HCs. However, BD patients did not display increased TL shortening relative to HCs. Studies that involve larger sample sizes and control for the heterogeneity of BD participants will be needed.},
}
RevDate: 2024-08-16
CmpDate: 2024-08-16
Causal relationship between telomere length and osteonecrosis: Bidirectional two-sample Mendelian randomization analysis.
Medicine, 103(33):e39324.
Recent mounting evidence suggests that shortening of telomere length (TL) is associated with impaired bone health; yet, a genetic causal relationship between TL and osteonecrosis remains uncertain. This study aimed to investigate the potential causal relationship between TL and osteonecrosis using bidirectional two-sample Mendelian randomization (MR). Genome-wide association study summary statistics for TL were sourced from the IEU Open genome-wide association study project, while osteonecrosis data were obtained from the FinnGen Biobank database. A range of MR methodologies-including inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode-were utilized for analysis, along with the MR-Egger intercept method for horizontal pleiotropy assessment, and Cochran Q and leave-one-out methods for heterogeneity testing. The forward MR analysis indicated a significant causal relationship between TL and osteonecrosis, suggesting that genetically predicted shorter TL is associated with an elevated risk of developing osteonecrosis (OR = 0.611, 95% confidence interval 0.394-0.948, P = .028). The reverse MR analysis revealed no significant influence of osteonecrosis on TL (OR = 0.999, 95% confidence interval 0.994-1.005, P = .802). Analyses for heterogeneity and horizontal pleiotropy yielded robust results. Our study demonstrates that individuals with shorter TL have an increased risk of developing osteonecrosis, whereas osteonecrosis has no effect on TL.
Additional Links: PMID-39151532
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@article {pmid39151532,
year = {2024},
author = {Liu, H and Yan, W and Li, J and Luo, D and Yan, D},
title = {Causal relationship between telomere length and osteonecrosis: Bidirectional two-sample Mendelian randomization analysis.},
journal = {Medicine},
volume = {103},
number = {33},
pages = {e39324},
doi = {10.1097/MD.0000000000039324},
pmid = {39151532},
issn = {1536-5964},
mesh = {*Mendelian Randomization Analysis ; Humans ; *Genome-Wide Association Study ; *Osteonecrosis/genetics ; Telomere Shortening/genetics ; Telomere/genetics ; Genetic Predisposition to Disease ; },
abstract = {Recent mounting evidence suggests that shortening of telomere length (TL) is associated with impaired bone health; yet, a genetic causal relationship between TL and osteonecrosis remains uncertain. This study aimed to investigate the potential causal relationship between TL and osteonecrosis using bidirectional two-sample Mendelian randomization (MR). Genome-wide association study summary statistics for TL were sourced from the IEU Open genome-wide association study project, while osteonecrosis data were obtained from the FinnGen Biobank database. A range of MR methodologies-including inverse variance weighting, MR-Egger, weighted median, simple mode, and weighted mode-were utilized for analysis, along with the MR-Egger intercept method for horizontal pleiotropy assessment, and Cochran Q and leave-one-out methods for heterogeneity testing. The forward MR analysis indicated a significant causal relationship between TL and osteonecrosis, suggesting that genetically predicted shorter TL is associated with an elevated risk of developing osteonecrosis (OR = 0.611, 95% confidence interval 0.394-0.948, P = .028). The reverse MR analysis revealed no significant influence of osteonecrosis on TL (OR = 0.999, 95% confidence interval 0.994-1.005, P = .802). Analyses for heterogeneity and horizontal pleiotropy yielded robust results. Our study demonstrates that individuals with shorter TL have an increased risk of developing osteonecrosis, whereas osteonecrosis has no effect on TL.},
}
MeSH Terms:
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*Mendelian Randomization Analysis
Humans
*Genome-Wide Association Study
*Osteonecrosis/genetics
Telomere Shortening/genetics
Telomere/genetics
Genetic Predisposition to Disease
RevDate: 2024-08-16
A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.
bioRxiv : the preprint server for biology pii:2024.08.05.606142.
Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (∼3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.
Additional Links: PMID-39149261
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@article {pmid39149261,
year = {2024},
author = {Porubsky, D and Dashnow, H and Sasani, TA and Logsdon, GA and Hallast, P and Noyes, MD and Kronenberg, ZN and Mokveld, T and Koundinya, N and Nolan, C and Steely, CJ and Guarracino, A and Dolzhenko, E and Harvey, WT and Rowell, WJ and Grigorev, K and Nicholas, TJ and Oshima, KK and Lin, J and Ebert, P and Watkins, WS and Leung, TY and Hanlon, VCT and McGee, S and Pedersen, BS and Goldberg, ME and Happ, HC and Jeong, H and Munson, KM and Hoekzema, K and Chan, DD and Wang, Y and Knuth, J and Garcia, GH and Fanslow, C and Lambert, C and Lee, C and Smith, JD and Levy, S and Mason, CE and Garrison, E and Lansdorp, PM and Neklason, DW and Jorde, LB and Quinlan, AR and Eberle, MA and Eichler, EE},
title = {A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.05.606142},
pmid = {39149261},
issn = {2692-8205},
abstract = {Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (∼3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.},
}
RevDate: 2024-08-15
A telomere-to-telomere cotton genome assembly reveals centromere evolution and a Mutator transposon-linked module regulating embryo development.
Nature genetics [Epub ahead of print].
Assembly of complete genomes can reveal functional genetic elements missing from draft sequences. Here we present the near-complete telomere-to-telomere and contiguous genome of the cotton species Gossypium raimondii. Our assembly identified gaps and misoriented or misassembled regions in previous assemblies and produced 13 centromeres, with 25 chromosomal ends having telomeres. In contrast to satellite-rich Arabidopsis and rice centromeres, cotton centromeres lack phased CENH3 nucleosome positioning patterns and probably evolved by invasion from long terminal repeat retrotransposons. In-depth expression profiling of transposable elements revealed a previously unannotated DNA transposon (MuTC01) that interacts with miR2947 to produce trans-acting small interfering RNAs (siRNAs), one of which targets the newly evolved LEC2 (LEC2b) to produce phased siRNAs. Systematic genome editing experiments revealed that this tripartite module, miR2947-MuTC01-LEC2b, controls the morphogenesis of complex folded embryos characteristic of Gossypium and its close relatives in the cotton tribe. Our study reveals a trans-acting siRNA-based tripartite regulatory pathway for embryo development in higher plants.
Additional Links: PMID-39147922
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@article {pmid39147922,
year = {2024},
author = {Huang, G and Bao, Z and Feng, L and Zhai, J and Wendel, JF and Cao, X and Zhu, Y},
title = {A telomere-to-telomere cotton genome assembly reveals centromere evolution and a Mutator transposon-linked module regulating embryo development.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {39147922},
issn = {1546-1718},
support = {32388101//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32201747//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Assembly of complete genomes can reveal functional genetic elements missing from draft sequences. Here we present the near-complete telomere-to-telomere and contiguous genome of the cotton species Gossypium raimondii. Our assembly identified gaps and misoriented or misassembled regions in previous assemblies and produced 13 centromeres, with 25 chromosomal ends having telomeres. In contrast to satellite-rich Arabidopsis and rice centromeres, cotton centromeres lack phased CENH3 nucleosome positioning patterns and probably evolved by invasion from long terminal repeat retrotransposons. In-depth expression profiling of transposable elements revealed a previously unannotated DNA transposon (MuTC01) that interacts with miR2947 to produce trans-acting small interfering RNAs (siRNAs), one of which targets the newly evolved LEC2 (LEC2b) to produce phased siRNAs. Systematic genome editing experiments revealed that this tripartite module, miR2947-MuTC01-LEC2b, controls the morphogenesis of complex folded embryos characteristic of Gossypium and its close relatives in the cotton tribe. Our study reveals a trans-acting siRNA-based tripartite regulatory pathway for embryo development in higher plants.},
}
RevDate: 2024-08-15
CmpDate: 2024-08-15
Multiple factors influence telomere length and DNA damage in individuals environmentally exposed to a coal-burning power plant.
Mutation research. Genetic toxicology and environmental mutagenesis, 898:503793.
Coal is a mixture of several chemicals, many of which have mutagenic and carcinogenic effects and are a key contributor to the global burden of mortality and disease. Previous studies suggest that coal is related to telomeric shortening in individuals occupationally exposed, however little is known about the effects of mining and burning coal on the telomeres of individuals living nearby. Therefore, the primary objective of this investigation was to assess the impact of proximity to coal power plants and coal mines on the genomic instability of individuals environmentally exposed, while also exploring potential associations with individual characteristics, oxidative stress, inflammatory responses, and the presence of inorganic elements. This study involved 80 men participants from three cities around a thermoelectric power plant and one city unexposed to coal and byproducts. DNA was extracted from peripheral blood samples obtained from each participant, and the telomeres length (TL) was assessed using quantitative real-time polymerase chain reaction (qPCR) methodology. No significant difference was observed between exposed individuals (6227 ± 2884 bp) when compared to the unexposed group (5638 ± 2452 bp). Nevertheless, TL decrease was associated with age and risk for cardiovascular disease; and longer TL was found to be linked with increased concentrations of silicon and phosphorus in blood samples. No correlations were observed between TL with comet assay (visual score), micronucleus test, oxidative stress, and inflammatory results. Additional research is required to ascertain the potential correlation between these changes and the onset of diseases and premature mortality.
Additional Links: PMID-39147445
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@article {pmid39147445,
year = {2024},
author = {Souza, MR and Garcia, ALH and Dalberto, D and Picinini, J and Touguinha, LBA and Salvador, M and da Silva, J},
title = {Multiple factors influence telomere length and DNA damage in individuals environmentally exposed to a coal-burning power plant.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {898},
number = {},
pages = {503793},
doi = {10.1016/j.mrgentox.2024.503793},
pmid = {39147445},
issn = {1879-3592},
mesh = {Humans ; Male ; *DNA Damage ; *Coal/adverse effects ; *Power Plants ; Middle Aged ; Adult ; *Environmental Exposure/adverse effects ; *Telomere/drug effects/genetics ; *Oxidative Stress/drug effects ; Telomere Shortening/drug effects ; Comet Assay ; Micronucleus Tests ; Coal Mining ; Occupational Exposure/adverse effects ; Aged ; Telomere Homeostasis/drug effects ; },
abstract = {Coal is a mixture of several chemicals, many of which have mutagenic and carcinogenic effects and are a key contributor to the global burden of mortality and disease. Previous studies suggest that coal is related to telomeric shortening in individuals occupationally exposed, however little is known about the effects of mining and burning coal on the telomeres of individuals living nearby. Therefore, the primary objective of this investigation was to assess the impact of proximity to coal power plants and coal mines on the genomic instability of individuals environmentally exposed, while also exploring potential associations with individual characteristics, oxidative stress, inflammatory responses, and the presence of inorganic elements. This study involved 80 men participants from three cities around a thermoelectric power plant and one city unexposed to coal and byproducts. DNA was extracted from peripheral blood samples obtained from each participant, and the telomeres length (TL) was assessed using quantitative real-time polymerase chain reaction (qPCR) methodology. No significant difference was observed between exposed individuals (6227 ± 2884 bp) when compared to the unexposed group (5638 ± 2452 bp). Nevertheless, TL decrease was associated with age and risk for cardiovascular disease; and longer TL was found to be linked with increased concentrations of silicon and phosphorus in blood samples. No correlations were observed between TL with comet assay (visual score), micronucleus test, oxidative stress, and inflammatory results. Additional research is required to ascertain the potential correlation between these changes and the onset of diseases and premature mortality.},
}
MeSH Terms:
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hide MeSH Terms
Humans
Male
*DNA Damage
*Coal/adverse effects
*Power Plants
Middle Aged
Adult
*Environmental Exposure/adverse effects
*Telomere/drug effects/genetics
*Oxidative Stress/drug effects
Telomere Shortening/drug effects
Comet Assay
Micronucleus Tests
Coal Mining
Occupational Exposure/adverse effects
Aged
Telomere Homeostasis/drug effects
RevDate: 2024-08-15
Genetic Testing for Rare Retinal Diseases in Telomere Biology Disorders.
JAMA ophthalmology pii:2822243 [Epub ahead of print].
Additional Links: PMID-39145950
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@article {pmid39145950,
year = {2024},
author = {da Cruz, NFS and Berrocal, AM},
title = {Genetic Testing for Rare Retinal Diseases in Telomere Biology Disorders.},
journal = {JAMA ophthalmology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaophthalmol.2024.2947},
pmid = {39145950},
issn = {2168-6173},
}
RevDate: 2024-08-15
Development and validation of a glioma prognostic model based on telomere-related genes and immune infiltration analysis.
Translational cancer research, 13(7):3182-3199.
BACKGROUND: Gliomas are the most prevalent primary brain tumors, and patients typically exhibit poor prognoses. Increasing evidence suggests that telomere maintenance mechanisms play a crucial role in glioma development. However, the prognostic value of telomere-related genes in glioma remains uncertain. This study aimed to construct a prognostic model of telomere-related genes and further elucidate the potential association between the two.
METHODS: We acquired RNA-seq data for low-grade glioma (LGG) and glioblastoma (GBM), along with corresponding clinical information from The Cancer Genome Atlas (TCGA) database, and normal brain tissue data from the Genotype-Tissue Expression (GTEX) database for differential analysis. Telomere-related genes were obtained from TelNet. Initially, we conducted a differential analysis on TCGA and GTEX data to identify differentially expressed telomere-related genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on these genes. Subsequently, univariate Cox analysis and log-rank tests were employed to obtain prognosis-related genes. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were sequentially utilized to construct prognostic models. The model's robustness was demonstrated using receiver operating characteristic (ROC) curve analysis, and multivariate Cox regression of risk scores for clinical characteristics and prognostic models were calculated to assess independent prognostic factors. The aforementioned results were validated using the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, the CIBERSORT algorithm analyzed differences in immune cell infiltration levels between high- and low-risk groups, and candidate genes were validated in the Human Protein Atlas (HPA) database.
RESULTS: Differential analysis yielded 496 differentially expressed telomere-related genes. GO and KEGG pathway analyses indicated that these genes were primarily involved in telomere-related biological processes and pathways. Subsequently, a prognostic model comprising ten telomere-related genes was constructed through univariate Cox regression analysis, log-rank test, LASSO regression analysis, and multivariate Cox regression analysis. Patients were stratified into high-risk and low-risk groups based on risk scores. Kaplan-Meier (K-M) survival analysis revealed worse outcomes in the high-risk group compared to the low-risk group, and establishing that this prognostic model was a significant independent prognostic factor for glioma patients. Lastly, immune infiltration analysis was conducted, uncovering notable differences in the proportion of multiple immune cell infiltrations between high- and low-risk groups, and eight candidate genes were verified in the HPA database.
CONCLUSIONS: This study successfully constructed a prognostic model of telomere-related genes, which can more accurately predict glioma patient prognosis, offer potential targets and a theoretical basis for glioma treatment, and serve as a reference for immunotherapy through immune infiltration analysis.
Additional Links: PMID-39145097
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@article {pmid39145097,
year = {2024},
author = {Liu, X and Wang, J and Su, D and Wang, Q and Li, M and Zuo, Z and Han, Q and Li, X and Zhen, F and Fan, M and Chen, T},
title = {Development and validation of a glioma prognostic model based on telomere-related genes and immune infiltration analysis.},
journal = {Translational cancer research},
volume = {13},
number = {7},
pages = {3182-3199},
pmid = {39145097},
issn = {2219-6803},
abstract = {BACKGROUND: Gliomas are the most prevalent primary brain tumors, and patients typically exhibit poor prognoses. Increasing evidence suggests that telomere maintenance mechanisms play a crucial role in glioma development. However, the prognostic value of telomere-related genes in glioma remains uncertain. This study aimed to construct a prognostic model of telomere-related genes and further elucidate the potential association between the two.
METHODS: We acquired RNA-seq data for low-grade glioma (LGG) and glioblastoma (GBM), along with corresponding clinical information from The Cancer Genome Atlas (TCGA) database, and normal brain tissue data from the Genotype-Tissue Expression (GTEX) database for differential analysis. Telomere-related genes were obtained from TelNet. Initially, we conducted a differential analysis on TCGA and GTEX data to identify differentially expressed telomere-related genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on these genes. Subsequently, univariate Cox analysis and log-rank tests were employed to obtain prognosis-related genes. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were sequentially utilized to construct prognostic models. The model's robustness was demonstrated using receiver operating characteristic (ROC) curve analysis, and multivariate Cox regression of risk scores for clinical characteristics and prognostic models were calculated to assess independent prognostic factors. The aforementioned results were validated using the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, the CIBERSORT algorithm analyzed differences in immune cell infiltration levels between high- and low-risk groups, and candidate genes were validated in the Human Protein Atlas (HPA) database.
RESULTS: Differential analysis yielded 496 differentially expressed telomere-related genes. GO and KEGG pathway analyses indicated that these genes were primarily involved in telomere-related biological processes and pathways. Subsequently, a prognostic model comprising ten telomere-related genes was constructed through univariate Cox regression analysis, log-rank test, LASSO regression analysis, and multivariate Cox regression analysis. Patients were stratified into high-risk and low-risk groups based on risk scores. Kaplan-Meier (K-M) survival analysis revealed worse outcomes in the high-risk group compared to the low-risk group, and establishing that this prognostic model was a significant independent prognostic factor for glioma patients. Lastly, immune infiltration analysis was conducted, uncovering notable differences in the proportion of multiple immune cell infiltrations between high- and low-risk groups, and eight candidate genes were verified in the HPA database.
CONCLUSIONS: This study successfully constructed a prognostic model of telomere-related genes, which can more accurately predict glioma patient prognosis, offer potential targets and a theoretical basis for glioma treatment, and serve as a reference for immunotherapy through immune infiltration analysis.},
}
RevDate: 2024-08-15
Telomere-related gene risk model for prognosis prediction in colorectal cancer.
Translational cancer research, 13(7):3495-3521.
BACKGROUND: Colorectal cancer (CRC) is the third-most prevalent cancer globally. The biological significance of telomeres in CRC carcinogenesis and progression is underscored by accumulating data. Nevertheless, not much is known about how telomere-related genes (TRGs) affect CRC prognosis. Therefore, the aim of this study was to investigate the role of TRGs in CRC prognosis.
METHODS: We retrospectively obtained the expression profiles and clinical data of CRC patients from public databases. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, we created a telomere-related risk model to predict survival outcomes, identifying ten telomere-related differentially expressed genes (TRDEGs). Based on TRDEGs, we stratified patients from The Cancer Genome Atlas (TCGA) into low- and high-risk subsets. Subsequently, we conducted comprehensive analyses, including survival assessment, immune cell infiltration, drug sensitivity, and prediction of molecular interactions using Kaplan-Meier curves, ESTIMATE, CIBERSORT, OncoPredict, and other approaches.
RESULTS: The model showed exceptional predictive accuracy for survival. Significant differences in survival were observed between the two groups of participants grouped according to the model (P<0.001), and this difference was further confirmed in the external validation set (GSE39582) (P=0.004). Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4[+] T cells, effector memory CD4[+] T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature's capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced.
CONCLUSIONS: Overall, we constructed a telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.
Additional Links: PMID-39145075
PubMed:
Citation:
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@article {pmid39145075,
year = {2024},
author = {Chen, H and Pan, Y and Lv, C and He, W and Wu, D and Xuan, Q},
title = {Telomere-related gene risk model for prognosis prediction in colorectal cancer.},
journal = {Translational cancer research},
volume = {13},
number = {7},
pages = {3495-3521},
pmid = {39145075},
issn = {2219-6803},
abstract = {BACKGROUND: Colorectal cancer (CRC) is the third-most prevalent cancer globally. The biological significance of telomeres in CRC carcinogenesis and progression is underscored by accumulating data. Nevertheless, not much is known about how telomere-related genes (TRGs) affect CRC prognosis. Therefore, the aim of this study was to investigate the role of TRGs in CRC prognosis.
METHODS: We retrospectively obtained the expression profiles and clinical data of CRC patients from public databases. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, we created a telomere-related risk model to predict survival outcomes, identifying ten telomere-related differentially expressed genes (TRDEGs). Based on TRDEGs, we stratified patients from The Cancer Genome Atlas (TCGA) into low- and high-risk subsets. Subsequently, we conducted comprehensive analyses, including survival assessment, immune cell infiltration, drug sensitivity, and prediction of molecular interactions using Kaplan-Meier curves, ESTIMATE, CIBERSORT, OncoPredict, and other approaches.
RESULTS: The model showed exceptional predictive accuracy for survival. Significant differences in survival were observed between the two groups of participants grouped according to the model (P<0.001), and this difference was further confirmed in the external validation set (GSE39582) (P=0.004). Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4[+] T cells, effector memory CD4[+] T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature's capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced.
CONCLUSIONS: Overall, we constructed a telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.},
}
RevDate: 2024-08-14
Maternal peripheral blood telomere length and preterm birth in African American women: a pilot study.
Archives of gynecology and obstetrics [Epub ahead of print].
PURPOSE: This study aimed to explore the association between preterm birth and telomere length of maternal peripheral blood in African American women.
METHODS: 78 African American women were recruited for this study between 2018 and 2023 from 2 prenatal clinics in central and east Texas. Participants provided blood samples and completed clinic questionnaires, with clinical data collected from their post-delivery medical records. Telomere length was measured using monochrome multiplex quantitative real-time polymerase chain reaction. Linear regression and multinomial logistic regression were used to analyze the association between telomere length and gestational length. Kruskal-Wallis's test and Fisher's exact test were used to compare preterm birth, early-term birth and full-term birth by telomere length, social-demographic characteristics, stress and discrimination.
RESULTS: The rates of preterm birth was higher in pregnant women with shorter telomeres. After adjusting for confounders, for every 10-units increase in the relative telomere-to-single-copy gene (T/S) ratio, gestational days increased by 1.090 days (90% CI 0.182, 1.997), and for every 10-units decrease in the T/S ratio, the odds of preterm birth was 2.664 (90% CI 1.064, 6.673) times greater than the odds of full-term birth. No statistically significant associations were observed between stress, discrimination, and either preterm birth or telomere length.
CONCLUSIONS: Maternal peripheral blood telomere shortening is associated with preterm birth, providing support to further explore the clinical utility of maternal telomere testing for prediction and early intervention of preterm birth and the study of biological mechanisms of spontaneous preterm birth.
Additional Links: PMID-39141123
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@article {pmid39141123,
year = {2024},
author = {Huang, W and Han, G and Taylor, BD and Neal, G and Kochan, K and Page, RL},
title = {Maternal peripheral blood telomere length and preterm birth in African American women: a pilot study.},
journal = {Archives of gynecology and obstetrics},
volume = {},
number = {},
pages = {},
pmid = {39141123},
issn = {1432-0711},
abstract = {PURPOSE: This study aimed to explore the association between preterm birth and telomere length of maternal peripheral blood in African American women.
METHODS: 78 African American women were recruited for this study between 2018 and 2023 from 2 prenatal clinics in central and east Texas. Participants provided blood samples and completed clinic questionnaires, with clinical data collected from their post-delivery medical records. Telomere length was measured using monochrome multiplex quantitative real-time polymerase chain reaction. Linear regression and multinomial logistic regression were used to analyze the association between telomere length and gestational length. Kruskal-Wallis's test and Fisher's exact test were used to compare preterm birth, early-term birth and full-term birth by telomere length, social-demographic characteristics, stress and discrimination.
RESULTS: The rates of preterm birth was higher in pregnant women with shorter telomeres. After adjusting for confounders, for every 10-units increase in the relative telomere-to-single-copy gene (T/S) ratio, gestational days increased by 1.090 days (90% CI 0.182, 1.997), and for every 10-units decrease in the T/S ratio, the odds of preterm birth was 2.664 (90% CI 1.064, 6.673) times greater than the odds of full-term birth. No statistically significant associations were observed between stress, discrimination, and either preterm birth or telomere length.
CONCLUSIONS: Maternal peripheral blood telomere shortening is associated with preterm birth, providing support to further explore the clinical utility of maternal telomere testing for prediction and early intervention of preterm birth and the study of biological mechanisms of spontaneous preterm birth.},
}
RevDate: 2024-08-13
The effects of the space environment on circadian rhythm and sleep in astronauts: An emphasis on the telomere length dynamics associated with sleep.
Additional Links: PMID-39137932
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@article {pmid39137932,
year = {2024},
author = {Xerfan, EMS and Tempaku, PF and Tufik, S and Andersen, ML},
title = {The effects of the space environment on circadian rhythm and sleep in astronauts: An emphasis on the telomere length dynamics associated with sleep.},
journal = {Journal of sleep research},
volume = {},
number = {},
pages = {e14312},
doi = {10.1111/jsr.14312},
pmid = {39137932},
issn = {1365-2869},
support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Associação Fundo de Incentivo à Pesquisa/ ; #2020/13467-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
}
RevDate: 2024-08-10
CmpDate: 2024-08-10
Telomere-to-telomere genome assembly of Eleocharis dulcis and expression profiles during corm development.
Scientific data, 11(1):869.
Eleocharis dulcis (Burm. f.) Trin. ex Hensch., commonly known as Chinese water chestnut, is a traditional aquatic vegetable in China, and now is widely cultivated throughout the world because of its high nutritional value and unique tastes. Here, we report the assembly of a 493.24 Mb telomere-to-telomere (T2T) genome of E. dulcis accomplished by integrating ONT ultra-long reads, PacBio long reads and Hi-C data. The reference genome was anchored onto 111 gap-free chromosomes, containing 48.31% repeat elements and 33,493 predicted protein-coding genes. Whole genome duplication (WGD) and inter-genomic synteny analyses indicated that chromosome breakage and genome duplication in E. dulcis possibly occurred multiple times during genome evolution after its divergence from a common ancestor with Rhynchospora breviuscula at ca. 35.6 Mya. A comparative time-course transcriptome analysis of corm development revealed different patterns of gene expression between cultivated and wild accessions with the highest number of differentially expressed genes (DEGs, 15,870) at the middle swelling stage and some of the DEGs were significantly enriched for starch metabolic process.
Additional Links: PMID-39127691
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@article {pmid39127691,
year = {2024},
author = {Chen, Y and Zhang, X and Wang, L and Fang, M and Lu, R and Ma, Y and Huang, Y and Chen, X and Sheng, W and Shi, L and Zheng, Z and Qiu, Y},
title = {Telomere-to-telomere genome assembly of Eleocharis dulcis and expression profiles during corm development.},
journal = {Scientific data},
volume = {11},
number = {1},
pages = {869},
pmid = {39127691},
issn = {2052-4463},
mesh = {*Telomere/genetics ; *Genome, Plant ; *Eleocharis/genetics/growth & development ; Transcriptome ; },
abstract = {Eleocharis dulcis (Burm. f.) Trin. ex Hensch., commonly known as Chinese water chestnut, is a traditional aquatic vegetable in China, and now is widely cultivated throughout the world because of its high nutritional value and unique tastes. Here, we report the assembly of a 493.24 Mb telomere-to-telomere (T2T) genome of E. dulcis accomplished by integrating ONT ultra-long reads, PacBio long reads and Hi-C data. The reference genome was anchored onto 111 gap-free chromosomes, containing 48.31% repeat elements and 33,493 predicted protein-coding genes. Whole genome duplication (WGD) and inter-genomic synteny analyses indicated that chromosome breakage and genome duplication in E. dulcis possibly occurred multiple times during genome evolution after its divergence from a common ancestor with Rhynchospora breviuscula at ca. 35.6 Mya. A comparative time-course transcriptome analysis of corm development revealed different patterns of gene expression between cultivated and wild accessions with the highest number of differentially expressed genes (DEGs, 15,870) at the middle swelling stage and some of the DEGs were significantly enriched for starch metabolic process.},
}
MeSH Terms:
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*Telomere/genetics
*Genome, Plant
*Eleocharis/genetics/growth & development
Transcriptome
RevDate: 2024-08-10
CmpDate: 2024-08-10
Telomere Length, Telomerase Activity, and Vaginal Microbiome in Patients with HPV-Related Precancerous Lesions.
International journal of molecular sciences, 25(15): pii:ijms25158158.
Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.
Additional Links: PMID-39125728
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PubMed:
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@article {pmid39125728,
year = {2024},
author = {Boniewska-Bernacka, E and Pańczyszyn, A and Głąb, G and Goc, A},
title = {Telomere Length, Telomerase Activity, and Vaginal Microbiome in Patients with HPV-Related Precancerous Lesions.},
journal = {International journal of molecular sciences},
volume = {25},
number = {15},
pages = {},
doi = {10.3390/ijms25158158},
pmid = {39125728},
issn = {1422-0067},
support = {P-2023-007//Institute of Medical Sciences, University of Opole, Opole, Poland./ ; },
mesh = {Humans ; Female ; *Telomerase/metabolism/genetics ; *Vagina/microbiology/virology ; *Microbiota/genetics ; *Papillomavirus Infections/virology/complications/genetics ; Adult ; *Telomere/metabolism/genetics ; Middle Aged ; *Precancerous Conditions/virology/microbiology/genetics/pathology ; *Uterine Cervical Neoplasms/virology/microbiology/genetics/pathology ; Telomere Homeostasis ; Papillomaviridae/genetics ; },
abstract = {Persistent high-risk human papillomaviruses (HR HPVs) infection leads to the development of squamous intraepithelial lesions in cervical cells that may lead to cancer. The telomere length, telomerase activity, and species composition of the vaginal microbiome may influence the dynamic of changes and the process of carcinogenesis. In the present study, we analyze relative telomere length (RTL), relative hTERT expression (gene for the telomerase component-reverse transcriptase) in cervical smear cells and vaginal microbiomes. Total RNA and DNA were isolated from tissue samples of 109 patients from the following groups: control, carrier, low-grade or high-grade squamous intraepithelial lesion (L SIL and H SIL, respectively), and cancer. The quantitative PCR method was used to measure telomere length and telomerase expression. Vaginal microbiome bacteria were divided into community state types using morphotype criteria. Significant differences between histopathology groups were confirmed for both relative telomere length and relative hTERT expression (p < 0.001 and p = 0.001, respectively). A significant difference in RTL was identified between carriers and H SIL (p adj < 0.001) groups, as well as between carriers and L SIL groups (p adj = 0.048). In both cases, RTL was lower among carriers. The highest relative hTERT expression level was recorded in the H SIL group, and the highest relative hTERT expression level was recorded between carriers and the H SIL group (p adj < 0.001). A correlation between genotype and biocenosis was identified for genotype 16+A (p < 0.001). The results suggest that identification of HPV infection, telomere length assessment, and hTERT expression measurement together may be more predictive than each of these analyses performed separately.},
}
MeSH Terms:
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Humans
Female
*Telomerase/metabolism/genetics
*Vagina/microbiology/virology
*Microbiota/genetics
*Papillomavirus Infections/virology/complications/genetics
Adult
*Telomere/metabolism/genetics
Middle Aged
*Precancerous Conditions/virology/microbiology/genetics/pathology
*Uterine Cervical Neoplasms/virology/microbiology/genetics/pathology
Telomere Homeostasis
Papillomaviridae/genetics
RevDate: 2024-08-10
CmpDate: 2024-08-10
The Impact of the Mediterranean Diet on Telomere Biology: Implications for Disease Management-A Narrative Review.
Nutrients, 16(15): pii:nu16152525.
INTRODUCTION: Telomeres are nucleoprotein complexes at the ends of chromosomes that are under the control of genetic and environmental triggers. Accelerated telomere shortening is causally implicated in the increasing incidence of diseases. The Mediterranean diet has recently been identified as one that confers protection against diseases. This review aimed to identify the effect of each component of the Mediterranean diet on telomere length dynamics, highlighting the underlying molecular mechanisms.
METHODS: PubMed was searched to identify relevant studies to extract data for conducting a narrative review.
RESULTS: The Mediterranean diet alleviates clinical manifestations in many diseases. Focusing on autoimmune diseases, the Mediterranean diet can be protective by preventing inflammation, mitochondrial malfunction, and abnormal telomerase activity. Also, each Mediterranean diet constituent seems to attenuate aging through the sustenance or elongation of telomere length, providing insights into the underlying molecular mechanisms. Polyphenols, vitamins, minerals, and fatty acids seem to be essential in telomere homeostasis, since they inhibit inflammatory responses, DNA damage, oxidative stress, mitochondrial malfunction, and cell death and induce telomerase activation.
CONCLUSIONS: The Mediterranean diet is beneficial for maintaining telomere dynamics and alleviating age-related illnesses. This review provides a comprehensive overview of cross-sectional, observational, and randomized controlled trials regarding the beneficial impact of every constituent in the Mediterranean diet on telomere length and chronic disease management.
Additional Links: PMID-39125404
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PubMed:
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@article {pmid39125404,
year = {2024},
author = {Baliou, S and Ioannou, P and Apetroaei, MM and Vakonaki, E and Fragkiadaki, P and Kirithras, E and Tzatzarakis, MN and Arsene, AL and Docea, AO and Tsatsakis, A},
title = {The Impact of the Mediterranean Diet on Telomere Biology: Implications for Disease Management-A Narrative Review.},
journal = {Nutrients},
volume = {16},
number = {15},
pages = {},
doi = {10.3390/nu16152525},
pmid = {39125404},
issn = {2072-6643},
mesh = {Humans ; *Diet, Mediterranean ; *Telomere ; Telomere Homeostasis ; Telomere Shortening ; Aging ; Telomerase/metabolism ; Disease Management ; Oxidative Stress ; Polyphenols ; Autoimmune Diseases ; },
abstract = {INTRODUCTION: Telomeres are nucleoprotein complexes at the ends of chromosomes that are under the control of genetic and environmental triggers. Accelerated telomere shortening is causally implicated in the increasing incidence of diseases. The Mediterranean diet has recently been identified as one that confers protection against diseases. This review aimed to identify the effect of each component of the Mediterranean diet on telomere length dynamics, highlighting the underlying molecular mechanisms.
METHODS: PubMed was searched to identify relevant studies to extract data for conducting a narrative review.
RESULTS: The Mediterranean diet alleviates clinical manifestations in many diseases. Focusing on autoimmune diseases, the Mediterranean diet can be protective by preventing inflammation, mitochondrial malfunction, and abnormal telomerase activity. Also, each Mediterranean diet constituent seems to attenuate aging through the sustenance or elongation of telomere length, providing insights into the underlying molecular mechanisms. Polyphenols, vitamins, minerals, and fatty acids seem to be essential in telomere homeostasis, since they inhibit inflammatory responses, DNA damage, oxidative stress, mitochondrial malfunction, and cell death and induce telomerase activation.
CONCLUSIONS: The Mediterranean diet is beneficial for maintaining telomere dynamics and alleviating age-related illnesses. This review provides a comprehensive overview of cross-sectional, observational, and randomized controlled trials regarding the beneficial impact of every constituent in the Mediterranean diet on telomere length and chronic disease management.},
}
MeSH Terms:
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hide MeSH Terms
Humans
*Diet, Mediterranean
*Telomere
Telomere Homeostasis
Telomere Shortening
Aging
Telomerase/metabolism
Disease Management
Oxidative Stress
Polyphenols
Autoimmune Diseases
RevDate: 2024-08-09
Comparing Length and Telomere Expression at Oral Precancerous and Cancerous Stages.
Iranian journal of pathology, 19(2):146-151.
BACKGROUND & OBJECTIVE: Telomeres consist of repetitive G-rich nucleotides located at the end of each chromosome, acting as protein binding sites. The aim of this study was to examine the differences in telomere length in blood, saliva, and tissue samples at various stages of oral precancerous and cancerous lesions.
METHODS: Samples of blood, tissue, and saliva were collected from patients with oral precancerous and cancerous lesions. DNA extraction was performed. Then, a TRAP assay was conducted to assess and compare the telomere length and telomerase expression.
RESULTS: The levels of telomerase activity (TA) in the DNA samples ranged from 0.19 to 6.91 (2.05+1.37) among oral squamous cell carcinoma (OSCC) patients and from 0.17 to 4.5 (0.28+4.25) among precancerous patients. A significant difference was observed in TA levels between OSCC and precancerous samples (t=3.9691, P= 0.0000).
CONCLUSION: Assessing the telomerase activity is crucial for studying the behavior of carcinoma in the clinical setting. The augmented telomerase expression and the length of telomere contribute to OSCC progression. Hence, this study adds a diagnostic tool that can serve as a biomarker for the early detection and prognosis of OSCC.
Additional Links: PMID-39118803
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@article {pmid39118803,
year = {2024},
author = {Samadi, FM and Suhail, S and Sonam, M and Ahmad, MK and Kumar, V and Chandra, S and Mohammad, S},
title = {Comparing Length and Telomere Expression at Oral Precancerous and Cancerous Stages.},
journal = {Iranian journal of pathology},
volume = {19},
number = {2},
pages = {146-151},
doi = {10.30699/IJP.2024.1996330.3081},
pmid = {39118803},
issn = {1735-5303},
abstract = {BACKGROUND & OBJECTIVE: Telomeres consist of repetitive G-rich nucleotides located at the end of each chromosome, acting as protein binding sites. The aim of this study was to examine the differences in telomere length in blood, saliva, and tissue samples at various stages of oral precancerous and cancerous lesions.
METHODS: Samples of blood, tissue, and saliva were collected from patients with oral precancerous and cancerous lesions. DNA extraction was performed. Then, a TRAP assay was conducted to assess and compare the telomere length and telomerase expression.
RESULTS: The levels of telomerase activity (TA) in the DNA samples ranged from 0.19 to 6.91 (2.05+1.37) among oral squamous cell carcinoma (OSCC) patients and from 0.17 to 4.5 (0.28+4.25) among precancerous patients. A significant difference was observed in TA levels between OSCC and precancerous samples (t=3.9691, P= 0.0000).
CONCLUSION: Assessing the telomerase activity is crucial for studying the behavior of carcinoma in the clinical setting. The augmented telomerase expression and the length of telomere contribute to OSCC progression. Hence, this study adds a diagnostic tool that can serve as a biomarker for the early detection and prognosis of OSCC.},
}
RevDate: 2024-08-08
Telomerase reverse transcriptase, a telomere length maintenance protein in alfalfa (Medicago sativa), confers Arabidopsis thaliana seeds aging tolerance via modulation of telomere length.
International journal of biological macromolecules pii:S0141-8130(24)05193-6 [Epub ahead of print].
Numerous studies have investigated seed aging, with a particular emphasis on the involvement of reactive oxygen species. Reactive oxygen species diffuse into the nucleus and damage telomeres, resulting in loss of genetic integrity. Telomerase reverse transcriptase (TERT) plays an essential role in maintaining plant genomic stability. Genome-wide analyses of TERT genes in alfalfa (Medicago sativa) have not yet been conducted, leaving a gap in our understanding of the mechanisms underlying seed aging associated with TERT genes. In this study, four MsTERT genes were identified in the alfalfa genome. The expression profiles of the four MsTERT genes during seed germination indicated that MS. gene79077 was significantly upregulated by seed aging. Transgenic seeds overexpressing MS. gene79077 in Arabidopsis exhibited enhanced tolerance to seed aging by reducing the levels of H2O2 and increasing telomere length and telomerase activity. Furthermore, transcript profiling of aging-treated Arabidopsis wild-type and overexpressing seeds showed an aging response in genes related to glutathione-dependent detoxification and antioxidant defense pathways. These results revealed that MS. gene79077 conferred Arabidopsis seed-aging tolerance via modulation of antioxidant defense and telomere homeostasis. This study provides a new way to understand stress-responsive MsTERT genes for the potential genetic improvement of seed vigor.
Additional Links: PMID-39116978
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PubMed:
Citation:
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@article {pmid39116978,
year = {2024},
author = {Sun, S and Ma, W and Mi, C and Mao, P},
title = {Telomerase reverse transcriptase, a telomere length maintenance protein in alfalfa (Medicago sativa), confers Arabidopsis thaliana seeds aging tolerance via modulation of telomere length.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {134388},
doi = {10.1016/j.ijbiomac.2024.134388},
pmid = {39116978},
issn = {1879-0003},
abstract = {Numerous studies have investigated seed aging, with a particular emphasis on the involvement of reactive oxygen species. Reactive oxygen species diffuse into the nucleus and damage telomeres, resulting in loss of genetic integrity. Telomerase reverse transcriptase (TERT) plays an essential role in maintaining plant genomic stability. Genome-wide analyses of TERT genes in alfalfa (Medicago sativa) have not yet been conducted, leaving a gap in our understanding of the mechanisms underlying seed aging associated with TERT genes. In this study, four MsTERT genes were identified in the alfalfa genome. The expression profiles of the four MsTERT genes during seed germination indicated that MS. gene79077 was significantly upregulated by seed aging. Transgenic seeds overexpressing MS. gene79077 in Arabidopsis exhibited enhanced tolerance to seed aging by reducing the levels of H2O2 and increasing telomere length and telomerase activity. Furthermore, transcript profiling of aging-treated Arabidopsis wild-type and overexpressing seeds showed an aging response in genes related to glutathione-dependent detoxification and antioxidant defense pathways. These results revealed that MS. gene79077 conferred Arabidopsis seed-aging tolerance via modulation of antioxidant defense and telomere homeostasis. This study provides a new way to understand stress-responsive MsTERT genes for the potential genetic improvement of seed vigor.},
}
RevDate: 2024-08-08
Nucleotide sugars correlate with leukocyte telomere length as part of a dyskeratosis congenita metabolomic plasma signature.
Haematologica [Epub ahead of print].
Not available.
Additional Links: PMID-39113664
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@article {pmid39113664,
year = {2024},
author = {Li, Y and Sági-Kiss, V and James, ELN and Dokal, I and Parkinson, KE and Bundy, JG},
title = {Nucleotide sugars correlate with leukocyte telomere length as part of a dyskeratosis congenita metabolomic plasma signature.},
journal = {Haematologica},
volume = {},
number = {},
pages = {},
doi = {10.3324/haematol.2023.284721},
pmid = {39113664},
issn = {1592-8721},
abstract = {Not available.},
}
RevDate: 2024-08-07
Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery.
Critical care (London, England), 28(1):267.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes virus-induced-senescence. There is an association between shorter telomere length (TL) in coronavirus disease 2019 (COVID-19) patients and hospitalization, severity, or even death. However, it remains unknown whether virus-induced-senescence is reversible. We aim to evaluate the dynamics of TL in COVID-19 patients 1 year after recovery from intensive care units (ICU). Longitudinal study enrolling 49 patients admitted to ICU due to COVID-19 (August 2020 to April 2021). Relative telomere length (RTL) quantification was carried out in whole blood by monochromatic multiplex real-time quantitative PCR (MMqPCR) assay at hospitalization (baseline) and 1 year after discharge (1-year visit). The association between RTL and ICU length of stay (LOS), invasive mechanical ventilation (IMV), prone position, and pulmonary fibrosis development at 1-year visit was evaluated. The median age was 60 years, 71.4% were males, median ICU-LOS was 12 days, 73.5% required IMV, and 38.8% required a prone position. Patients with longer ICU-LOS or who required IMV showed greater RTL shortening during follow-up. Patients who required pronation had a greater RTL shortening during follow-up. IMV patients who developed pulmonary fibrosis showed greater RTL reduction and shorter RTL at the 1-year visit. Patients with longer ICU-LOS and those who required IMV had a shorter RTL in peripheral blood, as observed 1 year after hospital discharge. Additionally, patients who required IMV and developed pulmonary fibrosis had greater telomere shortening, showing shorter telomeres at the 1-year visit. These patients may be more prone to develop cellular senescence and lung-related complications; therefore, closer monitoring may be needed.
Additional Links: PMID-39113075
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@article {pmid39113075,
year = {2024},
author = {Virseda-Berdices, A and Behar-Lagares, R and Martínez-González, O and Blancas, R and Bueno-Bustos, S and Brochado-Kith, O and Manteiga, E and Mallol Poyato, MJ and López Matamala, B and Martín Parra, C and Resino, S and Jiménez-Sousa, MÁ and Fernández-Rodríguez, A},
title = {Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery.},
journal = {Critical care (London, England)},
volume = {28},
number = {1},
pages = {267},
pmid = {39113075},
issn = {1466-609X},
support = {1.013.005//Fundación Universidad Alfonso X el Sabio/ ; CB21/13/00044//CIBER - Consorcio Centro de Investigación Biomédica en Red-(CB 2021), Instituo de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea - NextGenerationEU/ ; COV20/1144//Instituto de Salud Carlos III/ ; },
abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes virus-induced-senescence. There is an association between shorter telomere length (TL) in coronavirus disease 2019 (COVID-19) patients and hospitalization, severity, or even death. However, it remains unknown whether virus-induced-senescence is reversible. We aim to evaluate the dynamics of TL in COVID-19 patients 1 year after recovery from intensive care units (ICU). Longitudinal study enrolling 49 patients admitted to ICU due to COVID-19 (August 2020 to April 2021). Relative telomere length (RTL) quantification was carried out in whole blood by monochromatic multiplex real-time quantitative PCR (MMqPCR) assay at hospitalization (baseline) and 1 year after discharge (1-year visit). The association between RTL and ICU length of stay (LOS), invasive mechanical ventilation (IMV), prone position, and pulmonary fibrosis development at 1-year visit was evaluated. The median age was 60 years, 71.4% were males, median ICU-LOS was 12 days, 73.5% required IMV, and 38.8% required a prone position. Patients with longer ICU-LOS or who required IMV showed greater RTL shortening during follow-up. Patients who required pronation had a greater RTL shortening during follow-up. IMV patients who developed pulmonary fibrosis showed greater RTL reduction and shorter RTL at the 1-year visit. Patients with longer ICU-LOS and those who required IMV had a shorter RTL in peripheral blood, as observed 1 year after hospital discharge. Additionally, patients who required IMV and developed pulmonary fibrosis had greater telomere shortening, showing shorter telomeres at the 1-year visit. These patients may be more prone to develop cellular senescence and lung-related complications; therefore, closer monitoring may be needed.},
}
RevDate: 2024-08-07
Dietary Zinc Intake and the Association of Insulin Level and HOMA-IR with Telomere Shortening in Mexican Children.
Biological trace element research [Epub ahead of print].
PURPOSE: The relationship between dietary zinc (Zn) intake, metabolic diseases, and telomere length has been little explored in the children population. This observational cross-sectional study assesses the association between obesity (OB), cardiometabolic traits, telomere length, and dietary Zn intake in children with normal weight (NW) and OB from Mexico City.
METHODS: Anthropometric data, blood pressure, biochemical measurements, the homeostatic model assessment of insulin resistance (HOMA-IR) and leucocyte telomere length (determined by quantitative-PCR) were analyzed in 171 children with NW and 172 with OB. Furthermore, dietary Zn intake was evaluated in 117 children NW and 120 with OB.
RESULTS: Telomere shortening was associated with fasting plasma insulin (FPI) and HOMA-IR in NW (beta coefficient [β]FPI = -0.022 ± 0.008, p = 0.009; βHOMA-IR = -0.096 ± 0.040, p = 0.020) and OB (βFPI = -0.007 ± 0.002, p = 0.003; βHOMA-IR = -0.034 ± 0.012, p = 0.005) children. Dietary Zn intake resulted negatively associated with FPI (β = -2.418 ± 0.764, p = 0.002) and HOMA-IR (β = -0.399 ± 0.014, p = 0.009) in children with OB. Then, in children with OB, the association between FPI, HOMA-IR, and telomere shortening was evaluated separately in groups of low, medium, and high dietary Zn intake (according to tertiles). The association between FPI, HOMA-IR, and telomere shortening was not significant in the high Zn intake group (PFPI = 0.633; PHOMA-IR = 0.567).
CONCLUSION: Our results suggest that a high Zn intake may ameliorate the telomere shortening related to high FPI and HOMA-IR.
Additional Links: PMID-39110381
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Citation:
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@article {pmid39110381,
year = {2024},
author = {Vazquez-Moreno, M and Perales-Herrera, A and Ramírez-Silva, I and Martínez-Gómez, LE and García-Cerón, A and Paredes-Barrientos, JC and Hernández-Mendoza, H and Martinez-Garza, S and Murillo-Ortiz, B and Cruz, M},
title = {Dietary Zinc Intake and the Association of Insulin Level and HOMA-IR with Telomere Shortening in Mexican Children.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {39110381},
issn = {1559-0720},
support = {FIS/IMSS/PROT/PRIO/ 18/079//Instituto Mexicano del Seguro Social/ ; },
abstract = {PURPOSE: The relationship between dietary zinc (Zn) intake, metabolic diseases, and telomere length has been little explored in the children population. This observational cross-sectional study assesses the association between obesity (OB), cardiometabolic traits, telomere length, and dietary Zn intake in children with normal weight (NW) and OB from Mexico City.
METHODS: Anthropometric data, blood pressure, biochemical measurements, the homeostatic model assessment of insulin resistance (HOMA-IR) and leucocyte telomere length (determined by quantitative-PCR) were analyzed in 171 children with NW and 172 with OB. Furthermore, dietary Zn intake was evaluated in 117 children NW and 120 with OB.
RESULTS: Telomere shortening was associated with fasting plasma insulin (FPI) and HOMA-IR in NW (beta coefficient [β]FPI = -0.022 ± 0.008, p = 0.009; βHOMA-IR = -0.096 ± 0.040, p = 0.020) and OB (βFPI = -0.007 ± 0.002, p = 0.003; βHOMA-IR = -0.034 ± 0.012, p = 0.005) children. Dietary Zn intake resulted negatively associated with FPI (β = -2.418 ± 0.764, p = 0.002) and HOMA-IR (β = -0.399 ± 0.014, p = 0.009) in children with OB. Then, in children with OB, the association between FPI, HOMA-IR, and telomere shortening was evaluated separately in groups of low, medium, and high dietary Zn intake (according to tertiles). The association between FPI, HOMA-IR, and telomere shortening was not significant in the high Zn intake group (PFPI = 0.633; PHOMA-IR = 0.567).
CONCLUSION: Our results suggest that a high Zn intake may ameliorate the telomere shortening related to high FPI and HOMA-IR.},
}
RevDate: 2024-08-07
The pineapple reference genome: Telomere-to-telomere assembly, manually curated annotation, and comparative analysis.
Journal of integrative plant biology [Epub ahead of print].
Pineapple is the third most crucial tropical fruit worldwide and available in five varieties. Genomes of different pineapple varieties have been released to date; however, none of them are complete, with all exhibiting substantial gaps and representing only two of the five pineapple varieties. This significantly hinders the advancement of pineapple breeding efforts. In this study, we sequenced the genomes of three varieties: a wild pineapple variety, a fiber pineapple variety, and a globally cultivated edible pineapple variety. We constructed the first gap-free reference genome (Ref) for pineapple. By consolidating multiple sources of evidence and manually revising each gene structure annotation, we identified 26,656 protein-coding genes. The BUSCO evaluation indicated a completeness of 99.2%, demonstrating the high quality of the gene structure annotations in this genome. Utilizing these resources, we identified 7,209 structural variations across the three varieties. Approximately 30.8% of pineapple genes were located within ±5 kb of structural variations, including 30 genes associated with anthocyanin synthesis. Further analysis and functional experiments demonstrated that the high expression of AcMYB528 aligns with the accumulation of anthocyanins in the leaves, both of which may be affected by a 1.9-kb insertion fragment. In addition, we developed the Ananas Genome Database, which offers data browsing, retrieval, analysis, and download functions. The construction of this database addresses the lack of pineapple genome resource databases. In summary, we acquired a seamless pineapple reference genome with high-quality gene structure annotations, providing a solid foundation for pineapple genomics and a valuable reference for pineapple breeding.
Additional Links: PMID-39109967
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PubMed:
Citation:
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@article {pmid39109967,
year = {2024},
author = {Feng, J and Zhang, W and Chen, C and Liang, Y and Li, T and Wu, Y and Liu, H and Wu, J and Lin, W and Li, J and He, Y and He, J and Luan, A},
title = {The pineapple reference genome: Telomere-to-telomere assembly, manually curated annotation, and comparative analysis.},
journal = {Journal of integrative plant biology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jipb.13748},
pmid = {39109967},
issn = {1744-7909},
support = {32272677//National Natural Science Foundation of China/ ; 2019YFD1001104//National Key R&D Program of China/ ; 1630032024026//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 1630032024001//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 1630052023011//Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Tropical Agricultural Sciences/ ; 323QN279//Hainan Provincial Natural Science Foundation of China/ ; },
abstract = {Pineapple is the third most crucial tropical fruit worldwide and available in five varieties. Genomes of different pineapple varieties have been released to date; however, none of them are complete, with all exhibiting substantial gaps and representing only two of the five pineapple varieties. This significantly hinders the advancement of pineapple breeding efforts. In this study, we sequenced the genomes of three varieties: a wild pineapple variety, a fiber pineapple variety, and a globally cultivated edible pineapple variety. We constructed the first gap-free reference genome (Ref) for pineapple. By consolidating multiple sources of evidence and manually revising each gene structure annotation, we identified 26,656 protein-coding genes. The BUSCO evaluation indicated a completeness of 99.2%, demonstrating the high quality of the gene structure annotations in this genome. Utilizing these resources, we identified 7,209 structural variations across the three varieties. Approximately 30.8% of pineapple genes were located within ±5 kb of structural variations, including 30 genes associated with anthocyanin synthesis. Further analysis and functional experiments demonstrated that the high expression of AcMYB528 aligns with the accumulation of anthocyanins in the leaves, both of which may be affected by a 1.9-kb insertion fragment. In addition, we developed the Ananas Genome Database, which offers data browsing, retrieval, analysis, and download functions. The construction of this database addresses the lack of pineapple genome resource databases. In summary, we acquired a seamless pineapple reference genome with high-quality gene structure annotations, providing a solid foundation for pineapple genomics and a valuable reference for pineapple breeding.},
}
RevDate: 2024-08-07
Role of Telomere Length in Radiation Response of Hematopoietic Stem & Progenitor Cells in Newborns.
Fetal and pediatric pathology [Epub ahead of print].
OBJECTIVE: Wide inter-individual variations in ionizing radiation (IR) responses of neonatal hematopoietic system calls for identifying reliable biomarkers to effectively estimate radiation exposure damages in neonates.
METHODS: Association between telomere length (TL) at birth and radiation sensitivity of cord blood hematopoietic stem cells (HSC) from 166 healthy newborns were investigated by assessing their clonogenic differentiation. TL was determined as terminal restriction fragment (TRF) by Southern blot method.
RESULTS: TL correlated with surviving fractions of total progenitor colony forming cell (CFC) content at 0.75 Gy (p < 0.05), granulo-macrophagic lineage colony forming units (CFU-GM) at 0.75 Gy (p < 0.05) and erythroid burst forming unit (BFU-E) at 0.75 Gy (p < 0.05) & at 3 Gy (p < 0.05) of newborns.
CONCLUSION: Our results indicate risks for HSC clonogenic survival in neonates with shorter telomeres after IR exposure. These observations might aid in considering TL at birth as an assessment factor for radiation related hematopoietic challenges in children.
Additional Links: PMID-39108072
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PubMed:
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@article {pmid39108072,
year = {2024},
author = {Biswas, A and Bhattacharya, M and Ghosh, P and Dey, SK},
title = {Role of Telomere Length in Radiation Response of Hematopoietic Stem & Progenitor Cells in Newborns.},
journal = {Fetal and pediatric pathology},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/15513815.2024.2381752},
pmid = {39108072},
issn = {1551-3823},
abstract = {OBJECTIVE: Wide inter-individual variations in ionizing radiation (IR) responses of neonatal hematopoietic system calls for identifying reliable biomarkers to effectively estimate radiation exposure damages in neonates.
METHODS: Association between telomere length (TL) at birth and radiation sensitivity of cord blood hematopoietic stem cells (HSC) from 166 healthy newborns were investigated by assessing their clonogenic differentiation. TL was determined as terminal restriction fragment (TRF) by Southern blot method.
RESULTS: TL correlated with surviving fractions of total progenitor colony forming cell (CFC) content at 0.75 Gy (p < 0.05), granulo-macrophagic lineage colony forming units (CFU-GM) at 0.75 Gy (p < 0.05) and erythroid burst forming unit (BFU-E) at 0.75 Gy (p < 0.05) & at 3 Gy (p < 0.05) of newborns.
CONCLUSION: Our results indicate risks for HSC clonogenic survival in neonates with shorter telomeres after IR exposure. These observations might aid in considering TL at birth as an assessment factor for radiation related hematopoietic challenges in children.},
}
RevDate: 2024-08-06
Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.
Cell death and differentiation [Epub ahead of print].
Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.
Additional Links: PMID-39107495
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@article {pmid39107495,
year = {2024},
author = {Nai, S and Wang, M and Yang, J and Ling, B and Dong, Q and Yang, X and Du, X and Lu, M and Liu, L and Yu, Z and Chen, L},
title = {Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {39107495},
issn = {1476-5403},
abstract = {Erk signaling is indispensable for the self-renewal and differentiation of mouse embryonic stem cells (ESCs), as well as telomere homeostasis. But how Erk regulates these biological processes remains unclear. We identified 132 Erk2 interacting proteins by co-immunoprecipitation and mass spectrometric analysis, and focused on Ddx39 as a potential Erk2 substrate. We demonstrated that Erk2 phosphorylates Ddx39 on Y132 and Y138. Ddx39 knockout (KO) ESCs are defective in differentiation, due to reduced H3K27ac level upon differentiation. Phosphorylation of Ddx39 promotes the recruitment of Hat1 to acetylate H3K27 and activate differentiation genes. In addition, Ddx39 KO leads to telomere elongation in ESCs. Ddx39 is recruited to telomeres by the telomere-binding protein Trf1, consequently disrupting the DNA loop formed by Trf1 and suppressing the alternative lengthening of telomeres (ALT). Phosphorylation of Ddx39 weakens its interaction with Trf1, releasing it from telomeres. Thus, ALT activity is enhanced, and telomeres are elongated. Altogether, our studies reveal an essential role of Ddx39 in the differentiation and telomere homeostasis of ESCs.},
}
RevDate: 2024-08-05
The Ruminant Telomere-to-Telomere (RT2T) Consortium.
Nature genetics [Epub ahead of print].
Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.
Additional Links: PMID-39103649
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@article {pmid39103649,
year = {2024},
author = {Kalbfleisch, TS and McKay, SD and Murdoch, BM and Adelson, DL and Almansa-Villa, D and Becker, G and Beckett, LM and Benítez-Galeano, MJ and Biase, F and Casey, T and Chuong, E and Clark, E and Clarke, S and Cockett, N and Couldrey, C and Davis, BW and Elsik, CG and Faraut, T and Gao, Y and Genet, C and Grady, P and Green, J and Green, R and Guan, D and Hagen, D and Hartley, GA and Heaton, M and Hoyt, SJ and Huang, W and Jarvis, E and Kalleberg, J and Khatib, H and Koepfi, KP and Koltes, J and Koren, S and Kuehn, C and Leeb, T and Leonard, A and Liu, GE and Low, WY and McConnell, H and McRae, K and Miga, K and Mousel, M and Neibergs, H and Olagunju, T and Pennell, M and Petry, B and Pewsner, M and Phillippy, AM and Pickett, BD and Pineda, P and Potapova, T and Rachagani, S and Rhie, A and Rijnkels, M and Robic, A and Rodriguez Osorio, N and Safonova, Y and Schettini, G and Schnabel, RD and Sirpu Natesh, N and Stegemiller, M and Storer, J and Stothard, P and Stull, C and Tosser-Klopp, G and Traglia, GM and Tuggle, CK and Van Tassell, CP and Watson, C and Weikard, R and Wimmers, K and Xie, S and Yang, L and Smith, TPL and O'Neill, RJ and Rosen, BD},
title = {The Ruminant Telomere-to-Telomere (RT2T) Consortium.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {39103649},
issn = {1546-1718},
support = {Grant Number 2023-67015-39000//United States Department of Agriculture | Agricultural Research Service (USDA Agricultural Research Service)/ ; },
abstract = {Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.},
}
RevDate: 2024-08-05
Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia.
British journal of haematology [Epub ahead of print].
Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.
Additional Links: PMID-39103182
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PubMed:
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@article {pmid39103182,
year = {2024},
author = {Strauss, JD and Brown, DW and Zhou, W and Dagnall, C and Yuan, JM and Im, A and Savage, SA and Wang, Y and Rafati, M and Spellman, SR and Gadalla, SM},
title = {Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia.},
journal = {British journal of haematology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bjh.19681},
pmid = {39103182},
issn = {1365-2141},
support = {75N910D00024/CA/NCI NIH HHS/United States ; U24CA076518/CA/NCI NIH HHS/United States ; N00014-21-1-2954//Office of Naval Research/ ; N00014-23-1-2057//Office of Naval Research/ ; HHSH250201700006C/HRSA/HRSA HHS/United States ; //National Marrow Donor Program/ ; },
abstract = {Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.},
}
RevDate: 2024-08-05
Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study.
Heliyon, 10(14):e33854.
BACKGROUND: The link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed.
METHODS: We extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode.
RESULTS: Genetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes.
CONCLUSION: This study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.
Additional Links: PMID-39100478
PubMed:
Citation:
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@article {pmid39100478,
year = {2024},
author = {Wang, Y and Sun, F and Yue, C and Man, Q},
title = {Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study.},
journal = {Heliyon},
volume = {10},
number = {14},
pages = {e33854},
pmid = {39100478},
issn = {2405-8440},
abstract = {BACKGROUND: The link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed.
METHODS: We extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode.
RESULTS: Genetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes.
CONCLUSION: This study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.},
}
RevDate: 2024-08-04
Overexpression of protection of telomeres 1 (POT1), a single-stranded DNA-binding proteins in alfalfa (Medicago sativa), enhances seed vigor.
International journal of biological macromolecules, 277(Pt 3):134300 pii:S0141-8130(24)05105-5 [Epub ahead of print].
Extensive bodies of research are dedicated to the study of seed aging with a particular focus on the roles of reactive oxygen species (ROS), and the ensuing oxidative damage during storage, as a primary cause of seed vigor decreasing. ROS diffuse to the nucleus and damage the telomeres, resulting in a loss of genetic integrity. Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere region, and plays an essential role in maintaining genomic stability in plants. In this study, there were totally four MsPOT1 genes obtained from alfalfa genome. Expression analysis of four MsPOT1 genes in germinated seed presented the different expressions. Four MsPOT1 genes displayed high expression levels at the early stage of seed germination, Among the four POT1 genes, it was found that MS. gene040108 was significantly up-regulated in the early germination stage of CK seeds, but down-regulated in aged seeds. RT-qPCR assays and RNA-seq data revealed that MsPOT1-X gene was significantly induced by seed aging treatment. Transgenic seeds overexpressing MsPOT1-X gene in Arabidopsis thaliana and Medicago trunctula exhibited enhanced seed vigor, telomere length, telomerase activity associated with reduced H2O2 content. These results would provide a new way to understand aging stress-responsive MsPOT1 genes for genetic improvement of seed vigor. Although a key gene regulating seed vigor was identified in this study, the specific mechanism of MsPOT1-X gene regulating seed vigor needs to be further explored.
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@article {pmid39097069,
year = {2024},
author = {Sun, S and Ma, W and Mao, P},
title = {Overexpression of protection of telomeres 1 (POT1), a single-stranded DNA-binding proteins in alfalfa (Medicago sativa), enhances seed vigor.},
journal = {International journal of biological macromolecules},
volume = {277},
number = {Pt 3},
pages = {134300},
doi = {10.1016/j.ijbiomac.2024.134300},
pmid = {39097069},
issn = {1879-0003},
abstract = {Extensive bodies of research are dedicated to the study of seed aging with a particular focus on the roles of reactive oxygen species (ROS), and the ensuing oxidative damage during storage, as a primary cause of seed vigor decreasing. ROS diffuse to the nucleus and damage the telomeres, resulting in a loss of genetic integrity. Protection of telomeres 1 (POT1) is a telomeric protein that binds to the telomere region, and plays an essential role in maintaining genomic stability in plants. In this study, there were totally four MsPOT1 genes obtained from alfalfa genome. Expression analysis of four MsPOT1 genes in germinated seed presented the different expressions. Four MsPOT1 genes displayed high expression levels at the early stage of seed germination, Among the four POT1 genes, it was found that MS. gene040108 was significantly up-regulated in the early germination stage of CK seeds, but down-regulated in aged seeds. RT-qPCR assays and RNA-seq data revealed that MsPOT1-X gene was significantly induced by seed aging treatment. Transgenic seeds overexpressing MsPOT1-X gene in Arabidopsis thaliana and Medicago trunctula exhibited enhanced seed vigor, telomere length, telomerase activity associated with reduced H2O2 content. These results would provide a new way to understand aging stress-responsive MsPOT1 genes for genetic improvement of seed vigor. Although a key gene regulating seed vigor was identified in this study, the specific mechanism of MsPOT1-X gene regulating seed vigor needs to be further explored.},
}
RevDate: 2024-08-03
Clinical utility of relative telomere length analysis in pediatric bone marrow failure.
Blood cells, molecules & diseases, 109:102882 pii:S1079-9796(24)00060-3 [Epub ahead of print].
INTRODUCTION: Telomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases.
METHODOLOGY: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants.
RESULTS & CONCLUSION: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).
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@article {pmid39096784,
year = {2024},
author = {Amatya, S and Bhatia, P and Raina, S and Sreedharanunni, S and Singh, M and Rahman, E and Archana, MV and Trehan, A},
title = {Clinical utility of relative telomere length analysis in pediatric bone marrow failure.},
journal = {Blood cells, molecules & diseases},
volume = {109},
number = {},
pages = {102882},
doi = {10.1016/j.bcmd.2024.102882},
pmid = {39096784},
issn = {1096-0961},
abstract = {INTRODUCTION: Telomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases.
METHODOLOGY: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants.
RESULTS & CONCLUSION: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).},
}
RevDate: 2024-08-02
CmpDate: 2024-08-02
Telomere-to-telomere genome assembly of sorghum.
Scientific data, 11(1):835.
"Cuohu Bazi" (CHBZ) is an ancient sorghum variety collected from the fields of China, known for its agronomic traits like dwarf stature, early maturation. In this study, we present the first telomere-to-telomere (T2T) and gap-free genome assembly of CHBZ using PacBio HiFi reads, Oxford Nanopore Technologies, and Hi-C data. The assembled genome comprises 724.85 Mb, effectively resolving all 3,913 gaps that were present in the previous sorghum BTx623 reference genome. Notably, the T2T assembly captures 10 centromeres and all 20 telomeres, providing strong support for their integrity. This assembly is of high quality in terms of contiguity (contig N50: 71.1 Mb), completeness (BUSCO score: 99.01%, k-mer completeness: 98.88%), and correctness (QV: 61.60). Repetitive sequences accounted for 70.41% of the genome and a total of 32,855 protein-coding genes have been annotated. Furthermore, 161 CHBZ-specific presence/absence variants genes have been identified when comparing to BTx623 genome. This study provides valuable insights for future research on sorghum genetics, genomics, and evolutionary history.
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@article {pmid39095379,
year = {2024},
author = {Li, M and Chen, C and Wang, H and Qin, H and Hou, S and Yang, X and Jian, J and Gao, P and Liu, M and Mu, Z},
title = {Telomere-to-telomere genome assembly of sorghum.},
journal = {Scientific data},
volume = {11},
number = {1},
pages = {835},
pmid = {39095379},
issn = {2052-4463},
mesh = {*Sorghum/genetics ; *Genome, Plant ; *Telomere/genetics ; },
abstract = {"Cuohu Bazi" (CHBZ) is an ancient sorghum variety collected from the fields of China, known for its agronomic traits like dwarf stature, early maturation. In this study, we present the first telomere-to-telomere (T2T) and gap-free genome assembly of CHBZ using PacBio HiFi reads, Oxford Nanopore Technologies, and Hi-C data. The assembled genome comprises 724.85 Mb, effectively resolving all 3,913 gaps that were present in the previous sorghum BTx623 reference genome. Notably, the T2T assembly captures 10 centromeres and all 20 telomeres, providing strong support for their integrity. This assembly is of high quality in terms of contiguity (contig N50: 71.1 Mb), completeness (BUSCO score: 99.01%, k-mer completeness: 98.88%), and correctness (QV: 61.60). Repetitive sequences accounted for 70.41% of the genome and a total of 32,855 protein-coding genes have been annotated. Furthermore, 161 CHBZ-specific presence/absence variants genes have been identified when comparing to BTx623 genome. This study provides valuable insights for future research on sorghum genetics, genomics, and evolutionary history.},
}
MeSH Terms:
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*Sorghum/genetics
*Genome, Plant
*Telomere/genetics
RevDate: 2024-08-02
Pancreatitis as a Potential Consequence of Danazol Therapy for Telomere Biology Disorders.
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@article {pmid39093267,
year = {2024},
author = {McCullough, KB and Vege, SS and Mangaonkar, AA and Ferrer, A and Patnaik, MM},
title = {Pancreatitis as a Potential Consequence of Danazol Therapy for Telomere Biology Disorders.},
journal = {Mayo Clinic proceedings},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.mayocp.2024.03.019},
pmid = {39093267},
issn = {1942-5546},
}
RevDate: 2024-08-01
The association between telomere length and diabetes mellitus: accumulated evidence from observational studies.
The Journal of clinical endocrinology and metabolism pii:7725656 [Epub ahead of print].
OBJECTIVE: In order to assess the associations between telomere length (TL) and diabetes mellitus (DM), especially type 2 diabetes (T2DM), we performed this systematic review and meta-analysis.
METHODS: PubMed, Embase, and Web of Science were thoroughly searched up to July 11, 2023. The pooled standardized mean difference (SMD) and the 95% confidence interval (CI) were evaluated using the random-effects model. Age, sex, study design, duration of diabetes, region, sample size, and body mass index (BMI) were used to stratify subgroup analyses.
RESULTS: A total of 37 observational studies involving 18,181 participants from 14 countries were included in the quantitative meta-analysis. In this study, patients with diabetes had shorter TL than the non-diabetic, whether those patients had T1DM (-2.70; 95% CI: -4.47, -0.93; P<0.001), T2DM (-3.70; 95% CI: -4.20, -3.20; P<0.001), or other types of diabetes (-0.71; 95% CI: -1.10, -0.31; P<0.001). Additionally, subgroup analysis of T2DM showed that TL was significantly correlated with age, sex, study design, diabetes duration, sample size, detection method, region, and BMI.
CONCLUSION: A negative correlation was observed between TL and DM. To validate this association in the interim, more extensive, superior prospective investigations and clinical trials are required.
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@article {pmid39087945,
year = {2024},
author = {He, X and Cao, L and Fu, X and Wu, Y and Wen, H and Gao, Y and Huo, W and Wang, M and Liu, M and Su, Y and Liu, G and Zhang, M and Hu, F and Hu, D and Zhao, Y},
title = {The association between telomere length and diabetes mellitus: accumulated evidence from observational studies.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgae536},
pmid = {39087945},
issn = {1945-7197},
abstract = {OBJECTIVE: In order to assess the associations between telomere length (TL) and diabetes mellitus (DM), especially type 2 diabetes (T2DM), we performed this systematic review and meta-analysis.
METHODS: PubMed, Embase, and Web of Science were thoroughly searched up to July 11, 2023. The pooled standardized mean difference (SMD) and the 95% confidence interval (CI) were evaluated using the random-effects model. Age, sex, study design, duration of diabetes, region, sample size, and body mass index (BMI) were used to stratify subgroup analyses.
RESULTS: A total of 37 observational studies involving 18,181 participants from 14 countries were included in the quantitative meta-analysis. In this study, patients with diabetes had shorter TL than the non-diabetic, whether those patients had T1DM (-2.70; 95% CI: -4.47, -0.93; P<0.001), T2DM (-3.70; 95% CI: -4.20, -3.20; P<0.001), or other types of diabetes (-0.71; 95% CI: -1.10, -0.31; P<0.001). Additionally, subgroup analysis of T2DM showed that TL was significantly correlated with age, sex, study design, diabetes duration, sample size, detection method, region, and BMI.
CONCLUSION: A negative correlation was observed between TL and DM. To validate this association in the interim, more extensive, superior prospective investigations and clinical trials are required.},
}
RevDate: 2024-08-01
Casual effects of telomere length on sarcoidosis: a bidirectional Mendelian randomization analysis.
Frontiers in medicine, 11:1408980.
BACKGROUND: Telomere length, crucial for genomic stability, have been implicated in various inflamm-aging diseases, but their role in sarcoidosis remains unexplored.
OBJECTIVE: This study aims to explore the casual effects between TL and sarcoidosis via a bidirectional Mendelian Randomization (MR) study.
METHODS: We examined single nucleotide polymorphisms (SNPs) associated with TL and sarcoidosis, utilizing available open-access genome-wide association study (GWAS) databases from the UK Biobank and FinnGen. We employed five MR techniques, including Inverse Variance Weighted (IVW), MR Egger, weighted median (WM), Robust adjusted profile score (RAPS), and Maximum likelihood, to assess causal relationships and explore pleiotropy.
RESULTS: Summary data extracted from GWAS datasets of TL (n = 472,174) and (n = 217,758) of European ancestry. Employing 130 SNPs with genome-wide significance as instrumental factors for TL, we detect a significant negative correlation between TL and sarcoidosis (OR: 0.682, 95% confidence interval: 0.524-0.888, p : 0.0045). Similarly, utilizing 6 SNPs with genome-wide significance as instrumental factors for sarcoidosis, we fail to identify a noteworthy association between sarcoidosis and TL (OR: 0.992, 95% confidence interval: 0.979-1.005, p : 0.2424).
CONCLUSION: Our results suggest that longer telomeres may reduce the risk of sarcoidosis, highlighting TL as a potential biomarker for diagnosis and long-term monitoring. Understanding the critical role of telomere shortening enables more effective focus on diagnosing, treating, and curing sarcoidosis linked to telomeres. Clinical investigations into treatments that enhance TL are warranted.
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@article {pmid39086950,
year = {2024},
author = {Zhu, S and Hao, Z and Chen, Q and Liu, X and Wu, W and Luo, Y and Zhang, F},
title = {Casual effects of telomere length on sarcoidosis: a bidirectional Mendelian randomization analysis.},
journal = {Frontiers in medicine},
volume = {11},
number = {},
pages = {1408980},
pmid = {39086950},
issn = {2296-858X},
abstract = {BACKGROUND: Telomere length, crucial for genomic stability, have been implicated in various inflamm-aging diseases, but their role in sarcoidosis remains unexplored.
OBJECTIVE: This study aims to explore the casual effects between TL and sarcoidosis via a bidirectional Mendelian Randomization (MR) study.
METHODS: We examined single nucleotide polymorphisms (SNPs) associated with TL and sarcoidosis, utilizing available open-access genome-wide association study (GWAS) databases from the UK Biobank and FinnGen. We employed five MR techniques, including Inverse Variance Weighted (IVW), MR Egger, weighted median (WM), Robust adjusted profile score (RAPS), and Maximum likelihood, to assess causal relationships and explore pleiotropy.
RESULTS: Summary data extracted from GWAS datasets of TL (n = 472,174) and (n = 217,758) of European ancestry. Employing 130 SNPs with genome-wide significance as instrumental factors for TL, we detect a significant negative correlation between TL and sarcoidosis (OR: 0.682, 95% confidence interval: 0.524-0.888, p : 0.0045). Similarly, utilizing 6 SNPs with genome-wide significance as instrumental factors for sarcoidosis, we fail to identify a noteworthy association between sarcoidosis and TL (OR: 0.992, 95% confidence interval: 0.979-1.005, p : 0.2424).
CONCLUSION: Our results suggest that longer telomeres may reduce the risk of sarcoidosis, highlighting TL as a potential biomarker for diagnosis and long-term monitoring. Understanding the critical role of telomere shortening enables more effective focus on diagnosing, treating, and curing sarcoidosis linked to telomeres. Clinical investigations into treatments that enhance TL are warranted.},
}
RevDate: 2024-08-01
Associations of childhood and adulthood body size, and child-to-adult body size change with adult telomere length.
Diabetes, obesity & metabolism [Epub ahead of print].
AIM: To comprehensively examine the associations of childhood and adulthood body size, and child-to-adult body size change with adult leucocyte telomere length (LTL).
METHODS: We included 453 602 participants from the UK Biobank. Childhood body size at the age of 10 years was collected through a questionnaire. Adulthood body size was assessed using body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fat mass index (FMI), and fat-free mass index (FFMI).
RESULTS: Individuals with plumper body size in childhood exhibited shorter LTL in adulthood (-0.0086 [-0.0017, -0.0004]). Adulthood BMI (-0.0286 [-0.0315, -0.0258]), WC (-0.0271 [-0.0303, -0.0238]), WHR (-0.0269 [-0.0308, -0.0230]) and FMI (-0.0396 [-0.0438, -0.0351]) were negatively associated with LTL, whereas FFMI (0.0095 [0.0039, 0.0152]) was positively associated with LTL. Compared to individuals consistently having an average/normal weight in both childhood and adulthood, those who maintained or developed overweight/obesity from childhood to adulthood had a shorter adult LTL, regardless of childhood body size. Notably, the LTL shortening effect was not observed in individuals with plumper body size in childhood but normal weight in adulthood.
CONCLUSIONS: Childhood and adulthood obesity are both associated with LTL shortening in adulthood. Transitioning to or maintaining overweight/obese status from childhood to adulthood is associated with shorter adult LTL, whereas this effect can be reversed if plumper children become normal weight.
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@article {pmid39086030,
year = {2024},
author = {Liu, Q and Fan, G and Bi, J and Fang, Q and Luo, F and Huang, X and Li, H and Liu, B and Yan, L and Guo, W and Wang, Y and Song, L},
title = {Associations of childhood and adulthood body size, and child-to-adult body size change with adult telomere length.},
journal = {Diabetes, obesity & metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1111/dom.15825},
pmid = {39086030},
issn = {1463-1326},
support = {2023AFB663//Hubei Provincial Natural Science Foundation of China/ ; 82003479//National Natural Science Foundation of China/ ; 82073660//National Natural Science Foundation of China/ ; 2019M662646//China Postdoctoral Science Foundation/ ; 2020T130220//China Postdoctoral Science Foundation/ ; },
abstract = {AIM: To comprehensively examine the associations of childhood and adulthood body size, and child-to-adult body size change with adult leucocyte telomere length (LTL).
METHODS: We included 453 602 participants from the UK Biobank. Childhood body size at the age of 10 years was collected through a questionnaire. Adulthood body size was assessed using body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fat mass index (FMI), and fat-free mass index (FFMI).
RESULTS: Individuals with plumper body size in childhood exhibited shorter LTL in adulthood (-0.0086 [-0.0017, -0.0004]). Adulthood BMI (-0.0286 [-0.0315, -0.0258]), WC (-0.0271 [-0.0303, -0.0238]), WHR (-0.0269 [-0.0308, -0.0230]) and FMI (-0.0396 [-0.0438, -0.0351]) were negatively associated with LTL, whereas FFMI (0.0095 [0.0039, 0.0152]) was positively associated with LTL. Compared to individuals consistently having an average/normal weight in both childhood and adulthood, those who maintained or developed overweight/obesity from childhood to adulthood had a shorter adult LTL, regardless of childhood body size. Notably, the LTL shortening effect was not observed in individuals with plumper body size in childhood but normal weight in adulthood.
CONCLUSIONS: Childhood and adulthood obesity are both associated with LTL shortening in adulthood. Transitioning to or maintaining overweight/obese status from childhood to adulthood is associated with shorter adult LTL, whereas this effect can be reversed if plumper children become normal weight.},
}
RevDate: 2024-07-31
CoPixie, a novel algorithm for single-particle track colocalization, enables efficient quantification of telomerase dynamics at telomeres.
Nucleic acids research pii:7724681 [Epub ahead of print].
Single-particle imaging and tracking can be combined with colocalization analysis to study the dynamic interactions between macromolecules in living cells. Indeed, single-particle tracking has been extensively used to study protein-DNA interactions and dynamics. Still, unbiased identification and quantification of binding events at specific genomic loci remains challenging. Herein, we describe CoPixie, a new software that identifies colocalization events between a theoretically unlimited number of imaging channels, including single-particle movies. CoPixie is an object-based colocalization algorithm that relies on both pixel and trajectory overlap to determine colocalization between molecules. We employed CoPixie with live-cell single-molecule imaging of telomerase and telomeres, to test the model that cancer-associated POT1 mutations facilitate telomere accessibility. We show that POT1 mutants Y223C, D224N or K90E increase telomere accessibility for telomerase interaction. However, unlike the POT1-D224N mutant, the POT1-Y223C and POT1-K90E mutations also increase the duration of long-lasting telomerase interactions at telomeres. Our data reveal that telomere elongation in cells expressing cancer-associated POT1 mutants arises from the dual impact of these mutations on telomere accessibility and telomerase retention at telomeres. CoPixie can be used to explore a variety of questions involving macromolecular interactions in living cells, including between proteins and nucleic acids, from multicolor single-particle tracks.
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@article {pmid39082280,
year = {2024},
author = {Prince, S and Maguemoun, K and Ferdebouh, M and Querido, E and Derumier, A and Tremblay, S and Chartrand, P},
title = {CoPixie, a novel algorithm for single-particle track colocalization, enables efficient quantification of telomerase dynamics at telomeres.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae669},
pmid = {39082280},
issn = {1362-4962},
support = {PJT-162156/CAPMC/CIHR/Canada ; //Natural Sciences and Engineering Research Council of Canada/ ; //Fonds de recherche du Québec-Nature et technologies/ ; },
abstract = {Single-particle imaging and tracking can be combined with colocalization analysis to study the dynamic interactions between macromolecules in living cells. Indeed, single-particle tracking has been extensively used to study protein-DNA interactions and dynamics. Still, unbiased identification and quantification of binding events at specific genomic loci remains challenging. Herein, we describe CoPixie, a new software that identifies colocalization events between a theoretically unlimited number of imaging channels, including single-particle movies. CoPixie is an object-based colocalization algorithm that relies on both pixel and trajectory overlap to determine colocalization between molecules. We employed CoPixie with live-cell single-molecule imaging of telomerase and telomeres, to test the model that cancer-associated POT1 mutations facilitate telomere accessibility. We show that POT1 mutants Y223C, D224N or K90E increase telomere accessibility for telomerase interaction. However, unlike the POT1-D224N mutant, the POT1-Y223C and POT1-K90E mutations also increase the duration of long-lasting telomerase interactions at telomeres. Our data reveal that telomere elongation in cells expressing cancer-associated POT1 mutants arises from the dual impact of these mutations on telomere accessibility and telomerase retention at telomeres. CoPixie can be used to explore a variety of questions involving macromolecular interactions in living cells, including between proteins and nucleic acids, from multicolor single-particle tracks.},
}
RevDate: 2024-07-31
TRF2-RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM-DNA2-dependent 5'-end resection.
Nucleic acids research pii:7724679 [Epub ahead of print].
Inappropriate homology-directed repair (HDR) of telomeres results in catastrophic telomere loss and aberrant chromosome fusions, leading to genome instability. We have previously shown that the TRF2-RAP1 heterodimer protects telomeres from engaging in aberrant telomere HDR. Cells lacking the basic domain of TRF2 and functional RAP1 display HDR-mediated telomere clustering, resulting in the formation of ultrabright telomeres (UTs) and massive chromosome fusions. Using purified proteins, we uncover three distinct molecular pathways that the TRF2-RAP1 heterodimer utilizes to protect telomeres from engaging in aberrant HDR. We show mechanistically that TRF2-RAP1 inhibits RAD51-initiated telomeric D-loop formation. Both the TRF2 basic domain and RAP1-binding to TRF2 are required to block RAD51-mediated homology search. TRF2 recruits the BLM helicase to telomeres through its TRFH domain to promote BLM-mediated unwinding of telomere D-loops. In addition, TRF2-RAP1 inhibits BLM-DNA2-mediated 5' telomere end resection, preventing the generation of 3' single-stranded telomere overhangs necessary for RAD51-dependent HDR. Importantly, cells expressing BLM mutants unable to interact with TRF2 accumulate telomere D-loops and UTs. Our findings uncover distinct molecular mechanisms coordinated by TRF2-RAP1 to protect telomeres from engaging in aberrant HDR.
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@article {pmid39082275,
year = {2024},
author = {Liang, F and Rai, R and Sodeinde, T and Chang, S},
title = {TRF2-RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM-DNA2-dependent 5'-end resection.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae642},
pmid = {39082275},
issn = {1362-4962},
support = {W81XWH-22-1-0099//Department of Defense/ ; RO1GM141350/NH/NIH HHS/United States ; },
abstract = {Inappropriate homology-directed repair (HDR) of telomeres results in catastrophic telomere loss and aberrant chromosome fusions, leading to genome instability. We have previously shown that the TRF2-RAP1 heterodimer protects telomeres from engaging in aberrant telomere HDR. Cells lacking the basic domain of TRF2 and functional RAP1 display HDR-mediated telomere clustering, resulting in the formation of ultrabright telomeres (UTs) and massive chromosome fusions. Using purified proteins, we uncover three distinct molecular pathways that the TRF2-RAP1 heterodimer utilizes to protect telomeres from engaging in aberrant HDR. We show mechanistically that TRF2-RAP1 inhibits RAD51-initiated telomeric D-loop formation. Both the TRF2 basic domain and RAP1-binding to TRF2 are required to block RAD51-mediated homology search. TRF2 recruits the BLM helicase to telomeres through its TRFH domain to promote BLM-mediated unwinding of telomere D-loops. In addition, TRF2-RAP1 inhibits BLM-DNA2-mediated 5' telomere end resection, preventing the generation of 3' single-stranded telomere overhangs necessary for RAD51-dependent HDR. Importantly, cells expressing BLM mutants unable to interact with TRF2 accumulate telomere D-loops and UTs. Our findings uncover distinct molecular mechanisms coordinated by TRF2-RAP1 to protect telomeres from engaging in aberrant HDR.},
}
RevDate: 2024-07-31
Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.
Journal of blood medicine, 15:313-323 pii:462758.
Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.
Additional Links: PMID-39081620
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@article {pmid39081620,
year = {2024},
author = {Obeagu, EI and Obeagu, GU},
title = {Telomere Dynamics in Sickle Cell Anemia: Unraveling Molecular Aging and Disease Progression.},
journal = {Journal of blood medicine},
volume = {15},
number = {},
pages = {313-323},
doi = {10.2147/JBM.S462758},
pmid = {39081620},
issn = {1179-2736},
abstract = {Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.},
}
RevDate: 2024-07-30
Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.
Bone marrow transplantation [Epub ahead of print].
While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.
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@article {pmid39080469,
year = {2024},
author = {Hussein-Agha, R and Kannengiesser, C and Lainey, E and Marcais, A and Srour, M and Sterin, A and Buchbinder, N and Borie, R and Plessier, A and Socié, G and Peffault de Latour, R and Sicre de Fontbrune, F},
title = {Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.},
journal = {Bone marrow transplantation},
volume = {},
number = {},
pages = {},
pmid = {39080469},
issn = {1476-5365},
abstract = {While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.},
}
RevDate: 2024-07-29
Association between osteoporosis and the rate of telomere shortening.
Aging, 16: pii:206034 [Epub ahead of print].
A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.
Additional Links: PMID-39074257
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@article {pmid39074257,
year = {2024},
author = {Han, MH and Kwon, HS and Hwang, M and Park, HH and Jeong, JH and Park, KW and Kim, EJ and Yoon, SJ and Yoon, B and Jang, JW and Hong, JY and Choi, SH and Koh, SH},
title = {Association between osteoporosis and the rate of telomere shortening.},
journal = {Aging},
volume = {16},
number = {},
pages = {},
doi = {10.18632/aging.206034},
pmid = {39074257},
issn = {1945-4589},
abstract = {A shorter leukocyte telomere length (LTL) is reported to be associated with age-related diseases, including osteoporosis. Many studies have tried identifying the association between LTL and osteoporosis, although it remains controversial. This study aimed to determine whether osteoporosis is independently associated with LTL shortening in a prospective longitudinal cohort. The KBASE study is an independent multicenter prospective cohort in South Korea, which began in 2014. We compared the LTL values for each participant at baseline and over a 2-year follow-up period. Boxplots were used to demonstrate the differences in the change in LTL over a 2-year follow-up according to osteoporosis. Multivariable linear regression was conducted to identify whether osteoporosis is independently associated with the rate of telomere shortening. A total of 233 subjects (from 55 to 88 years) from the KBASE cohort were finally enrolled in the study. We observed that the LTL decreased by approximately 1.2 kbp over 2 years. While the LTL decreased as age increased, the rate of LTL shortening did not increase with age. Multivariable linear regression analysis indicated that only osteoporosis was independently associated with rapid LTL shortening over 2 years (B, -8.08; p = 0.038). We sought to identify an association between osteoporosis and LTL shortening in an independent prospective cohort. We found that participants with osteoporosis had significantly faster LTL shortening over 2 years than those without osteoporosis. We hope this study will help elucidate the underlying mechanisms in the relationship between LTL and osteoporosis in the future.},
}
RevDate: 2024-07-28
Exposure to four typical heavy metals induced telomere shortening of peripheral blood mononuclear cells in relevant with declined urinary aMT6s in rats.
Ecotoxicology and environmental safety, 283:116791 pii:S0147-6513(24)00867-4 [Epub ahead of print].
Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1β, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.
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@article {pmid39068742,
year = {2024},
author = {Chen, X and Ren, Q and Wu, F and Zhu, K and Tao, J and Zhang, A},
title = {Exposure to four typical heavy metals induced telomere shortening of peripheral blood mononuclear cells in relevant with declined urinary aMT6s in rats.},
journal = {Ecotoxicology and environmental safety},
volume = {283},
number = {},
pages = {116791},
doi = {10.1016/j.ecoenv.2024.116791},
pmid = {39068742},
issn = {1090-2414},
abstract = {Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1β, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.},
}
RevDate: 2024-07-27
Pharmacotherapeutic Considerations on Telomere Biology: The Positive Effect of Pharmacologically Active Substances on Telomere Length.
International journal of molecular sciences, 25(14): pii:ijms25147694.
Telomeres are part of chromatin structures containing repeated DNA sequences, which function as protective caps at the ends of chromosomes and prevent DNA degradation and recombination, thus ensuring the integrity of the genome. While telomere length (TL) can be genetically inherited, TL shortening has been associated with ageing and multiple xenobiotics and bioactive substances. TL has been characterised as a reliable biomarker for the predisposition to developing chronic pathologies and their progression. This narrative review aims to provide arguments in favour of including TL measurements in a complex prognostic and diagnostic panel of chronic pathologies and the importance of assessing the effect of different pharmacologically active molecules on the biology of telomeres. Medicines used in the management of cardiovascular diseases, diabetes, schizophrenia, hormone replacement therapy at menopause, danazol, melatonin, and probiotics have been studied for their positive protective effects against TL shortening. All these classes of drugs are analysed in the present review, with a particular focus on the molecular mechanisms involved.
Additional Links: PMID-39062937
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@article {pmid39062937,
year = {2024},
author = {Apetroaei, MM and Fragkiadaki, P and Velescu, BȘ and Baliou, S and Renieri, E and Dinu-Pirvu, CE and Drăgănescu, D and Vlăsceanu, AM and Nedea, MII and Udeanu, DI and Docea, AO and Tsatsakis, A and Arsene, AL},
title = {Pharmacotherapeutic Considerations on Telomere Biology: The Positive Effect of Pharmacologically Active Substances on Telomere Length.},
journal = {International journal of molecular sciences},
volume = {25},
number = {14},
pages = {},
doi = {10.3390/ijms25147694},
pmid = {39062937},
issn = {1422-0067},
abstract = {Telomeres are part of chromatin structures containing repeated DNA sequences, which function as protective caps at the ends of chromosomes and prevent DNA degradation and recombination, thus ensuring the integrity of the genome. While telomere length (TL) can be genetically inherited, TL shortening has been associated with ageing and multiple xenobiotics and bioactive substances. TL has been characterised as a reliable biomarker for the predisposition to developing chronic pathologies and their progression. This narrative review aims to provide arguments in favour of including TL measurements in a complex prognostic and diagnostic panel of chronic pathologies and the importance of assessing the effect of different pharmacologically active molecules on the biology of telomeres. Medicines used in the management of cardiovascular diseases, diabetes, schizophrenia, hormone replacement therapy at menopause, danazol, melatonin, and probiotics have been studied for their positive protective effects against TL shortening. All these classes of drugs are analysed in the present review, with a particular focus on the molecular mechanisms involved.},
}
RevDate: 2024-07-26
5-aza-2'-deoxycytidine induces telomere dysfunction in breast cancer cells.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 178:117173 pii:S0753-3322(24)01057-6 [Epub ahead of print].
AIMS: Azacitidine, a drug that epigenetically modifies DNA, is widely used to treat haematological malignancies. However, at low doses, it demethylates DNA, and as a result, can alter gene expression. In our previous publication, we showed that low doses of azacitidine induce telomere length elongation in breast cancer cells. In this study, we aim to identify the mechanisms which lead to telomere length increases.
METHODS: Breast cancer cell lines representing different molecular sub-types were exposed to 5-aza-2'-deoxycytidine (5-aza) in 2 and 3D cultures, followed by DNA, RNA, and protein extractions. Samples were then analysed for telomere length, DNA damage, telomerase, and ALT activity.
RESULTS: We show that treatment of the cell lines with 5-aza for 72 h induced DNA damage at the telomeres and increased ALT activity 3-fold. We also identified a gene, POLD3, which may be involved in the ALT activity seen after treatment.
CONCLUSION: Our results indicate that while 5-aza is a useful drug for treating haematological cancers, surviving cancer cells that have been exposed to lower doses of the drug may activate mechanisms such as ALT. This could lead to cancer cell survival and possible resistance to 5-aza clinically.
Additional Links: PMID-39059352
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@article {pmid39059352,
year = {2024},
author = {Al-Dulaimi, S and Matta, S and Slijepcevic, P and Roberts, T},
title = {5-aza-2'-deoxycytidine induces telomere dysfunction in breast cancer cells.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {178},
number = {},
pages = {117173},
doi = {10.1016/j.biopha.2024.117173},
pmid = {39059352},
issn = {1950-6007},
abstract = {AIMS: Azacitidine, a drug that epigenetically modifies DNA, is widely used to treat haematological malignancies. However, at low doses, it demethylates DNA, and as a result, can alter gene expression. In our previous publication, we showed that low doses of azacitidine induce telomere length elongation in breast cancer cells. In this study, we aim to identify the mechanisms which lead to telomere length increases.
METHODS: Breast cancer cell lines representing different molecular sub-types were exposed to 5-aza-2'-deoxycytidine (5-aza) in 2 and 3D cultures, followed by DNA, RNA, and protein extractions. Samples were then analysed for telomere length, DNA damage, telomerase, and ALT activity.
RESULTS: We show that treatment of the cell lines with 5-aza for 72 h induced DNA damage at the telomeres and increased ALT activity 3-fold. We also identified a gene, POLD3, which may be involved in the ALT activity seen after treatment.
CONCLUSION: Our results indicate that while 5-aza is a useful drug for treating haematological cancers, surviving cancer cells that have been exposed to lower doses of the drug may activate mechanisms such as ALT. This could lead to cancer cell survival and possible resistance to 5-aza clinically.},
}
RevDate: 2024-07-26
The Impact of HIV and Parasite Single Infection and Coinfection on Telomere Length: A Systematic Review.
Current issues in molecular biology, 46(7):7258-7290 pii:cimb46070431.
HIV and parasite infections accelerate biological aging, resulting in immune senescence, apoptosis and cellular damage. Telomere length is considered to be one of the most effective biomarkers of biological aging. HIV and parasite infection have been reported to shorten telomere length in the host. This systematic review aimed to highlight work that explored the influence of HIV and parasite single infections and coinfection on telomere length. Using specific keywords related to the topic of interest, an electronic search of several online databases (Google Scholar, Web of Science, Scopus, Science Direct and PubMed) was conducted to extract eligible articles. The association between HIV infection or parasite infection and telomere length and the association between HIV and parasite coinfection and telomere length were assessed independently. The studies reported were mostly conducted in the European countries. Of the 42 eligible research articles reviewed, HIV and parasite single infections were independently associated with telomere length shortening. Some studies found no association between antiretroviral therapy (ART) and telomere length shortening, while others found an association between ART and telomere length shortening. No studies reported on the association between HIV and parasite coinfection and telomere length. HIV and parasite infections independently accelerate telomere length shortening and biological aging. It is possible that coinfection with HIV and parasites may further accelerate telomere length shortening; however, this is a neglected field of research with no reported studies to date.
Additional Links: PMID-39057072
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@article {pmid39057072,
year = {2024},
author = {Macamo, ED and Mkhize-Kwitshana, ZL and Mthombeni, J and Naidoo, P},
title = {The Impact of HIV and Parasite Single Infection and Coinfection on Telomere Length: A Systematic Review.},
journal = {Current issues in molecular biology},
volume = {46},
number = {7},
pages = {7258-7290},
doi = {10.3390/cimb46070431},
pmid = {39057072},
issn = {1467-3045},
support = {HDID5149/KR/2021//SAMRC/ ; },
abstract = {HIV and parasite infections accelerate biological aging, resulting in immune senescence, apoptosis and cellular damage. Telomere length is considered to be one of the most effective biomarkers of biological aging. HIV and parasite infection have been reported to shorten telomere length in the host. This systematic review aimed to highlight work that explored the influence of HIV and parasite single infections and coinfection on telomere length. Using specific keywords related to the topic of interest, an electronic search of several online databases (Google Scholar, Web of Science, Scopus, Science Direct and PubMed) was conducted to extract eligible articles. The association between HIV infection or parasite infection and telomere length and the association between HIV and parasite coinfection and telomere length were assessed independently. The studies reported were mostly conducted in the European countries. Of the 42 eligible research articles reviewed, HIV and parasite single infections were independently associated with telomere length shortening. Some studies found no association between antiretroviral therapy (ART) and telomere length shortening, while others found an association between ART and telomere length shortening. No studies reported on the association between HIV and parasite coinfection and telomere length. HIV and parasite infections independently accelerate telomere length shortening and biological aging. It is possible that coinfection with HIV and parasites may further accelerate telomere length shortening; however, this is a neglected field of research with no reported studies to date.},
}
RevDate: 2024-07-26
Telomere Length in a South African Population Co-Infected with HIV and Helminths.
Current issues in molecular biology, 46(7):6853-6867 pii:cimb46070409.
Biological ageing refers to the gradual decrease in physiological functions, resulting in immune senescence, cellular damage and apoptosis. Telomere length is a biomarker of biological ageing. Limited studies have associated shorter telomere length with HIV and parasite single infections, with no studies reporting the association of HIV and parasite co-infection with telomere length. The study aimed to investigate whether telomere length shortening is accelerated in a South African population co-infected with HIV and helminths compared to participants singly infected with either HIV or helminths. Additionally, telomere length data were compared with participants' biochemical and full blood count parameters. A total of 200 participants were in groups of uninfected control, HIV single infection, helminth single infection and HIV and helminth co-infection groups. Relative telomere length (RTL) was determined using Real-Time PCR and associated with biochemical and full blood count parameters using multivariate regression analysis models that were adjusted for confounders. The uninfected control group was used as a reference group. The uninfected control group had the highest mean RTL (1.21 ± 0.53) while the HIV-infected (0.96 ± 0.42) and co-infected (0.93 ± 0.41) groups had similar RTLs, and lastly, the helminth-infected group (0.83 ± 0.33) had the lowest RTL (p = 0.0002). When compared to the uninfected control group, a significant association between RTL and biochemical parameters, including blood iron (β = -0.48), ferritin (β = -0.48), transferrin saturation (β = -0.57), transferrin (β = -0.57), phosphate (β = -0.47), vitamin A (β = -0.49) and C-reactive protein (β = -0.52) were noted in the co-infected group (p < 0.05). In addition, a significant association between RTL and full blood count, including (β = -0.47), haematocrit (β = -0.46), mean corpuscular volume (β = -0.47), lymphocytes (β = -0.45), mean corpuscular haemoglobin concentration (β = -0.45), red cell distribution width (β = -0.47), monocytes (β = -0.45), eosinophils (β = -0.45), basophils (β = -0.44) and transferrin saturation (β = -0.57) were also noted in the co-infected group (p < 0.05). Accelerated biological ageing, as indicated by telomere length shortening, is associated with HIV and helminth co-infections.
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@article {pmid39057051,
year = {2024},
author = {Macamo, ED and Mkhize-Kwitshana, ZL and Duma, Z and Mthombeni, J and Naidoo, P},
title = {Telomere Length in a South African Population Co-Infected with HIV and Helminths.},
journal = {Current issues in molecular biology},
volume = {46},
number = {7},
pages = {6853-6867},
doi = {10.3390/cimb46070409},
pmid = {39057051},
issn = {1467-3045},
support = {HDID5149/KR/202//SAMRC/ ; },
abstract = {Biological ageing refers to the gradual decrease in physiological functions, resulting in immune senescence, cellular damage and apoptosis. Telomere length is a biomarker of biological ageing. Limited studies have associated shorter telomere length with HIV and parasite single infections, with no studies reporting the association of HIV and parasite co-infection with telomere length. The study aimed to investigate whether telomere length shortening is accelerated in a South African population co-infected with HIV and helminths compared to participants singly infected with either HIV or helminths. Additionally, telomere length data were compared with participants' biochemical and full blood count parameters. A total of 200 participants were in groups of uninfected control, HIV single infection, helminth single infection and HIV and helminth co-infection groups. Relative telomere length (RTL) was determined using Real-Time PCR and associated with biochemical and full blood count parameters using multivariate regression analysis models that were adjusted for confounders. The uninfected control group was used as a reference group. The uninfected control group had the highest mean RTL (1.21 ± 0.53) while the HIV-infected (0.96 ± 0.42) and co-infected (0.93 ± 0.41) groups had similar RTLs, and lastly, the helminth-infected group (0.83 ± 0.33) had the lowest RTL (p = 0.0002). When compared to the uninfected control group, a significant association between RTL and biochemical parameters, including blood iron (β = -0.48), ferritin (β = -0.48), transferrin saturation (β = -0.57), transferrin (β = -0.57), phosphate (β = -0.47), vitamin A (β = -0.49) and C-reactive protein (β = -0.52) were noted in the co-infected group (p < 0.05). In addition, a significant association between RTL and full blood count, including (β = -0.47), haematocrit (β = -0.46), mean corpuscular volume (β = -0.47), lymphocytes (β = -0.45), mean corpuscular haemoglobin concentration (β = -0.45), red cell distribution width (β = -0.47), monocytes (β = -0.45), eosinophils (β = -0.45), basophils (β = -0.44) and transferrin saturation (β = -0.57) were also noted in the co-infected group (p < 0.05). Accelerated biological ageing, as indicated by telomere length shortening, is associated with HIV and helminth co-infections.},
}
RevDate: 2024-07-26
CmpDate: 2024-07-26
Association between telomere length and erectile dysfunction: a cross-sectional study.
Frontiers in endocrinology, 15:1391013.
BACKGROUND: Leukocyte telomere length (LTL) serves as a significant biomarker of aging. Erectile dysfunction (ED) is a commonly observed condition among middle-aged and older men. The objective of this study is to explore the potential association between LTL and ED.
METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES) to examine the association between LTL and ED. Weighted multivariate regression analyses were performed as the primary statistical method. Subgroup analyses were conducted to investigate specific population subsets, and restricted cubic spline (RCS) analyses were employed to assess the non-linear relationship between LTL and ED.
RESULTS: The results of weighted multivariate regression analyses revealed a negative correlation between LTL and the risk of ED. Individuals with ED exhibited shorter LTL compared to those without ED. For each unit increase in LTL, there was a 54% reduction in the risk of ED (odds ratios[OR] 0.46, 95% confidence intervals[CI] 0.25-0.85). When LTL was considered as a categorical variable, the group with the longest LTL (Q5) had a 44% lower risk of ED compared to the group with the shortest LTL(Q1) (OR 0.56, 95% CI 0.39-0.81). A non-linear relationship was observed between TL and ED. Various sensitivity analyses were conducted to validate the stability of the results, and consistent findings were obtained.
CONCLUSION: The negative association between leukocyte LTL and ED suggests that delaying the shortening of LTL may decrease the risk of ED.
Additional Links: PMID-39055058
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@article {pmid39055058,
year = {2024},
author = {Chen, X and Liu, B and Zhou, J and Lin, J and Jiang, W and Xie, R},
title = {Association between telomere length and erectile dysfunction: a cross-sectional study.},
journal = {Frontiers in endocrinology},
volume = {15},
number = {},
pages = {1391013},
doi = {10.3389/fendo.2024.1391013},
pmid = {39055058},
issn = {1664-2392},
mesh = {Humans ; Male ; *Erectile Dysfunction ; Cross-Sectional Studies ; Middle Aged ; *Telomere ; Leukocytes/metabolism/pathology ; Aged ; Adult ; Nutrition Surveys ; Telomere Homeostasis ; Telomere Shortening ; Risk Factors ; },
abstract = {BACKGROUND: Leukocyte telomere length (LTL) serves as a significant biomarker of aging. Erectile dysfunction (ED) is a commonly observed condition among middle-aged and older men. The objective of this study is to explore the potential association between LTL and ED.
METHODS: We utilized data from the National Health and Nutrition Examination Survey (NHANES) to examine the association between LTL and ED. Weighted multivariate regression analyses were performed as the primary statistical method. Subgroup analyses were conducted to investigate specific population subsets, and restricted cubic spline (RCS) analyses were employed to assess the non-linear relationship between LTL and ED.
RESULTS: The results of weighted multivariate regression analyses revealed a negative correlation between LTL and the risk of ED. Individuals with ED exhibited shorter LTL compared to those without ED. For each unit increase in LTL, there was a 54% reduction in the risk of ED (odds ratios[OR] 0.46, 95% confidence intervals[CI] 0.25-0.85). When LTL was considered as a categorical variable, the group with the longest LTL (Q5) had a 44% lower risk of ED compared to the group with the shortest LTL(Q1) (OR 0.56, 95% CI 0.39-0.81). A non-linear relationship was observed between TL and ED. Various sensitivity analyses were conducted to validate the stability of the results, and consistent findings were obtained.
CONCLUSION: The negative association between leukocyte LTL and ED suggests that delaying the shortening of LTL may decrease the risk of ED.},
}
MeSH Terms:
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Humans
Male
*Erectile Dysfunction
Cross-Sectional Studies
Middle Aged
*Telomere
Leukocytes/metabolism/pathology
Aged
Adult
Nutrition Surveys
Telomere Homeostasis
Telomere Shortening
Risk Factors
RevDate: 2024-07-26
Sleep is associated with telomere shortening: A population-based longitudinal study.
Journal of sleep research [Epub ahead of print].
As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.
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@article {pmid39054789,
year = {2024},
author = {Tempaku, PF and D'Almeida, V and Andersen, ML and Tufik, S},
title = {Sleep is associated with telomere shortening: A population-based longitudinal study.},
journal = {Journal of sleep research},
volume = {},
number = {},
pages = {e14274},
doi = {10.1111/jsr.14274},
pmid = {39054789},
issn = {1365-2869},
support = {#23/08657-0 to VDA//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; #20/13467-8 to MLA//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.},
}
RevDate: 2024-07-25
CmpDate: 2024-07-25
Use of peptide nucleic acid probe to determine telomere dynamics in improving chromosome analysis in genetic toxicology studies.
Mutation research. Genetic toxicology and environmental mutagenesis, 897:503773.
Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.
Additional Links: PMID-39054004
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@article {pmid39054004,
year = {2024},
author = {Ng, GYQ and Hande, MP},
title = {Use of peptide nucleic acid probe to determine telomere dynamics in improving chromosome analysis in genetic toxicology studies.},
journal = {Mutation research. Genetic toxicology and environmental mutagenesis},
volume = {897},
number = {},
pages = {503773},
doi = {10.1016/j.mrgentox.2024.503773},
pmid = {39054004},
issn = {1879-3592},
mesh = {*Peptide Nucleic Acids ; *Telomere/drug effects/genetics ; Humans ; *In Situ Hybridization, Fluorescence/methods ; Animals ; Mutagens/toxicity ; Karyotyping/methods ; },
abstract = {Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.},
}
MeSH Terms:
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*Peptide Nucleic Acids
*Telomere/drug effects/genetics
Humans
*In Situ Hybridization, Fluorescence/methods
Animals
Mutagens/toxicity
Karyotyping/methods
RevDate: 2024-07-25
CmpDate: 2024-07-25
Design and characterization of hyperactive mutants of the Agrobacterium tumefaciens telomere resolvase, TelA.
PloS one, 19(7):e0307590 pii:PONE-D-24-17544.
Telomere resolvases are a family of DNA cleavage and rejoining enzymes that produce linear DNAs terminated by hairpin telomeres from replicated intermediates in bacteria that possess linear replicons. The telomere resolvase of Agrobacterium tumefaciens, TelA, has been examined at the structural and biochemical level. The N-terminal domain of TelA, while not required for telomere resolution, has been demonstrated to play an autoinhibitory role in telomere resolution, conferring divalent metal responsiveness on the reaction. The N-terminal domain also inhibits the competing reactions of hp telomere fusion and recombination between replicated telomere junctions. Due to the absence of the N-terminal domain from TelA/DNA co-crystal structures we produced an AlphaFold model of a TelA monomer. The AlphaFold model suggested the presence of two inhibitory interfaces; one between the N-terminal domain and the catalytic domain and a second interface between the C-terminal helix and the N-core domain of the protein. We produced mutant TelA's designed to weaken these putative interfaces to test the validity of the modeled interfaces. While our analysis did not bear out the details of the predicted interfaces the model was, nonetheless, extremely useful in guiding design of mutations that, when combined, demonstrated an additive activation of TelA exceeding 250-fold. For some of these hyperactive mutants stimulation of telomere resolution has also been accompanied by activation of competing reactions. However, we have also characterized hyperactive TelA mutants that retain enough autoinhibition to suppress the competing reactions.
Additional Links: PMID-39052566
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@article {pmid39052566,
year = {2024},
author = {Huang, SH and Abrametz, K and McGrath, SL and Kobryn, K},
title = {Design and characterization of hyperactive mutants of the Agrobacterium tumefaciens telomere resolvase, TelA.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0307590},
doi = {10.1371/journal.pone.0307590},
pmid = {39052566},
issn = {1932-6203},
mesh = {*Agrobacterium tumefaciens/genetics/enzymology ; *Telomere/metabolism/genetics ; *Bacterial Proteins/genetics/metabolism/chemistry ; Mutation ; Models, Molecular ; },
abstract = {Telomere resolvases are a family of DNA cleavage and rejoining enzymes that produce linear DNAs terminated by hairpin telomeres from replicated intermediates in bacteria that possess linear replicons. The telomere resolvase of Agrobacterium tumefaciens, TelA, has been examined at the structural and biochemical level. The N-terminal domain of TelA, while not required for telomere resolution, has been demonstrated to play an autoinhibitory role in telomere resolution, conferring divalent metal responsiveness on the reaction. The N-terminal domain also inhibits the competing reactions of hp telomere fusion and recombination between replicated telomere junctions. Due to the absence of the N-terminal domain from TelA/DNA co-crystal structures we produced an AlphaFold model of a TelA monomer. The AlphaFold model suggested the presence of two inhibitory interfaces; one between the N-terminal domain and the catalytic domain and a second interface between the C-terminal helix and the N-core domain of the protein. We produced mutant TelA's designed to weaken these putative interfaces to test the validity of the modeled interfaces. While our analysis did not bear out the details of the predicted interfaces the model was, nonetheless, extremely useful in guiding design of mutations that, when combined, demonstrated an additive activation of TelA exceeding 250-fold. For some of these hyperactive mutants stimulation of telomere resolution has also been accompanied by activation of competing reactions. However, we have also characterized hyperactive TelA mutants that retain enough autoinhibition to suppress the competing reactions.},
}
MeSH Terms:
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*Agrobacterium tumefaciens/genetics/enzymology
*Telomere/metabolism/genetics
*Bacterial Proteins/genetics/metabolism/chemistry
Mutation
Models, Molecular
RevDate: 2024-07-26
Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma.
Heliyon, 10(13):e33525.
Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026). TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.
Additional Links: PMID-39050459
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@article {pmid39050459,
year = {2024},
author = {Tomasova, K and Seborova, K and Kroupa, M and Horak, J and Kavec, M and Vodickova, L and Rob, L and Hruda, M and Mrhalova, M and Bartakova, A and Bouda, J and Fleischer, T and Kristensen, VN and Vodicka, P and Vaclavikova, R},
title = {Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma.},
journal = {Heliyon},
volume = {10},
number = {13},
pages = {e33525},
pmid = {39050459},
issn = {2405-8440},
abstract = {Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026). TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.},
}
RevDate: 2024-07-24
Unlocking plant genetics with telomere-to-telomere genome assemblies.
Nature genetics [Epub ahead of print].
Contiguous genome sequence assemblies will help us to realize the full potential of crop translational genomics. Recent advances in sequencing technologies, especially long-read sequencing strategies, have made it possible to construct gapless telomere-to-telomere (T2T) assemblies, thus offering novel insights into genome organization and function. Plant genomes pose unique challenges, such as a continuum of ancient to recent polyploidy and abundant highly similar and long repetitive elements. Owing to progress in sequencing approaches, for most crop plants, chromosome-scale reference genome assemblies are available, but T2T assembly construction remains challenging. Here we describe methods for haplotype-resolved, gapless T2T assembly construction in plants, including various crop species. We outline the impact of T2T assemblies in elucidating the roles of repetitive elements in gene regulation, as well as in pangenomics, functional genomics, genome-assisted breeding and targeted genome manipulation. In conjunction with sequence-enriched germplasm repositories, T2T assemblies thus hold great promise for basic and applied plant sciences.
Additional Links: PMID-39048791
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@article {pmid39048791,
year = {2024},
author = {Garg, V and Bohra, A and Mascher, M and Spannagl, M and Xu, X and Bevan, MW and Bennetzen, JL and Varshney, RK},
title = {Unlocking plant genetics with telomere-to-telomere genome assemblies.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {39048791},
issn = {1546-1718},
abstract = {Contiguous genome sequence assemblies will help us to realize the full potential of crop translational genomics. Recent advances in sequencing technologies, especially long-read sequencing strategies, have made it possible to construct gapless telomere-to-telomere (T2T) assemblies, thus offering novel insights into genome organization and function. Plant genomes pose unique challenges, such as a continuum of ancient to recent polyploidy and abundant highly similar and long repetitive elements. Owing to progress in sequencing approaches, for most crop plants, chromosome-scale reference genome assemblies are available, but T2T assembly construction remains challenging. Here we describe methods for haplotype-resolved, gapless T2T assembly construction in plants, including various crop species. We outline the impact of T2T assemblies in elucidating the roles of repetitive elements in gene regulation, as well as in pangenomics, functional genomics, genome-assisted breeding and targeted genome manipulation. In conjunction with sequence-enriched germplasm repositories, T2T assemblies thus hold great promise for basic and applied plant sciences.},
}
RevDate: 2024-07-24
Short leukocyte telomere length and high plasma phospholipid fatty acids increase the risk of type 2 diabetes.
Endocrine connections pii:EC-24-0033 [Epub ahead of print].
In the last forty years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effect of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL.Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.
Additional Links: PMID-39045889
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@article {pmid39045889,
year = {2024},
author = {Yang, C and Zhang, Y and Li, J and Liu, X and Qiu, J and Zhang, J and Liu, X and Zhang, Y and Zhao, Y},
title = {Short leukocyte telomere length and high plasma phospholipid fatty acids increase the risk of type 2 diabetes.},
journal = {Endocrine connections},
volume = {},
number = {},
pages = {},
doi = {10.1530/EC-24-0033},
pmid = {39045889},
issn = {2049-3614},
abstract = {In the last forty years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effect of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL.Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.},
}
RevDate: 2024-07-24
The association of metabolic syndrome with telomere length as a marker of cellular aging: a systematic review and meta-analysis.
Frontiers in genetics, 15:1390198.
BACKGROUND: It has been suggested that metabolic syndrome (MetS) accelerates the aging process, potentially contributing to the development of age-related complications. Available studies examining the relation of MetS to telomere length (TL), a putative biological marker of aging, have yielded inconclusive findings. This meta-analysis was performed to investigate the association between MetS and TL.
METHODS: A comprehensive systematic search was conducted in PubMed and Scopus databases to identify relevant literature published up to February 2024. Standard mean difference (SMD) and standardized beta coefficient (β) with their 95% confidence intervals (CI) were used as effect sizes to measure the associations using the random effects model.
RESULTS: A total of nine studies, comprising a total sample size of 8,606 participants, were eligible for the meta-analysis. No significant difference in mean TL was found between patients with and without MetS (SMD = -0.03, 95%CI = -0.17 to 0.10), with a significant heterogeneity across the studies (I [2] = 89.7.0%, p ≤ 0.001). In contrast, it was revealed that MetS is negatively related to TL (β = -0.08, 95%CI = -0.15 to -0.004). In the subgroup analysis, this finding was supported by the International Diabetes Federation (IDF) definition of MetS.
CONCLUSION: This meta-analysis highlighted that MetS may be linked to a shorter TL. Additional studies are required to confirm this finding.
Additional Links: PMID-39045323
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@article {pmid39045323,
year = {2024},
author = {Ibraheem Shelash Al-Hawary, S and Ali Alzahrani, A and Ghaleb Maabreh, H and Abed Jawad, M and Alsaadi, SB and Kareem Jabber, N and Alawadi, A and Alsalamy, A and Alizadeh, F},
title = {The association of metabolic syndrome with telomere length as a marker of cellular aging: a systematic review and meta-analysis.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1390198},
pmid = {39045323},
issn = {1664-8021},
abstract = {BACKGROUND: It has been suggested that metabolic syndrome (MetS) accelerates the aging process, potentially contributing to the development of age-related complications. Available studies examining the relation of MetS to telomere length (TL), a putative biological marker of aging, have yielded inconclusive findings. This meta-analysis was performed to investigate the association between MetS and TL.
METHODS: A comprehensive systematic search was conducted in PubMed and Scopus databases to identify relevant literature published up to February 2024. Standard mean difference (SMD) and standardized beta coefficient (β) with their 95% confidence intervals (CI) were used as effect sizes to measure the associations using the random effects model.
RESULTS: A total of nine studies, comprising a total sample size of 8,606 participants, were eligible for the meta-analysis. No significant difference in mean TL was found between patients with and without MetS (SMD = -0.03, 95%CI = -0.17 to 0.10), with a significant heterogeneity across the studies (I [2] = 89.7.0%, p ≤ 0.001). In contrast, it was revealed that MetS is negatively related to TL (β = -0.08, 95%CI = -0.15 to -0.004). In the subgroup analysis, this finding was supported by the International Diabetes Federation (IDF) definition of MetS.
CONCLUSION: This meta-analysis highlighted that MetS may be linked to a shorter TL. Additional studies are required to confirm this finding.},
}
RevDate: 2024-07-24
Telomere Length as a Marker of Suicidal Risk in Schizophrenia.
Consortium psychiatricum, 3(2):37-47.
BACKGROUND: Schizophrenia and suicidal behavior are associated with shortening in the length of telomeres. The aim of the study was to compare the content (pg/mcg) of telomeric repeat in DNA isolated from peripheral blood cells in three groups of subjects: patients with schizophrenia and a history of suicide attempts, patients with schizophrenia without suicidal tendencies, and healthy control volunteers.
METHODS: Relapses according to gender and age were examined in 47 patients with schizophrenia with suicidal behavior, 47 patients without self-destructive conditions, and 47 volunteers with healthy control and maintenance for the content of telomeric and the number of copies of mitochondrial DNA (mtDNA) in peripheral blood leukocytes.
RESULTS: Analysis of determining the content of telomeric repeat (TR) in the DNA of massive weight gain in the series: patients with schizophrenia and suicidal attempts - patients with schizophrenia without suicidal observations - healthy controls (225±28.4 (227 [190; 250]) vs. 243±21 (245 [228; 260]) vs. 255±17.9 (255 [242; 266]), p <0.005. The same trend is observed for the number of mtDNA copies (257±101.5 (250 [194; 297])) vs. 262.3±59.3 (254 [217; 312]) vs. 272±79.9 (274 [213; 304]); p=0.012), but no significant differences were recorded.
CONCLUSIONS: For the first time, the phenomenon of telomere shortening was discovered in schizophrenics with suicidal risk. The length of the telomere corresponds to the parameter of a biological marker - an objectively measured indicator of normal or pathological processes, but gaining an idea of its reliability is still necessary for verification with an assessment of its sensitivity, specificity, and positive and negative predictive value. The telomere may be considered a putative predictive indicator of suicidal risk.
Additional Links: PMID-39045115
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@article {pmid39045115,
year = {2022},
author = {Zakharova, N and Bravve, L and Mamedova, G and Kaydan, M and Ershova, E and Martynov, A and Veiko, N and Kostyuk, S},
title = {Telomere Length as a Marker of Suicidal Risk in Schizophrenia.},
journal = {Consortium psychiatricum},
volume = {3},
number = {2},
pages = {37-47},
pmid = {39045115},
issn = {2713-2919},
abstract = {BACKGROUND: Schizophrenia and suicidal behavior are associated with shortening in the length of telomeres. The aim of the study was to compare the content (pg/mcg) of telomeric repeat in DNA isolated from peripheral blood cells in three groups of subjects: patients with schizophrenia and a history of suicide attempts, patients with schizophrenia without suicidal tendencies, and healthy control volunteers.
METHODS: Relapses according to gender and age were examined in 47 patients with schizophrenia with suicidal behavior, 47 patients without self-destructive conditions, and 47 volunteers with healthy control and maintenance for the content of telomeric and the number of copies of mitochondrial DNA (mtDNA) in peripheral blood leukocytes.
RESULTS: Analysis of determining the content of telomeric repeat (TR) in the DNA of massive weight gain in the series: patients with schizophrenia and suicidal attempts - patients with schizophrenia without suicidal observations - healthy controls (225±28.4 (227 [190; 250]) vs. 243±21 (245 [228; 260]) vs. 255±17.9 (255 [242; 266]), p <0.005. The same trend is observed for the number of mtDNA copies (257±101.5 (250 [194; 297])) vs. 262.3±59.3 (254 [217; 312]) vs. 272±79.9 (274 [213; 304]); p=0.012), but no significant differences were recorded.
CONCLUSIONS: For the first time, the phenomenon of telomere shortening was discovered in schizophrenics with suicidal risk. The length of the telomere corresponds to the parameter of a biological marker - an objectively measured indicator of normal or pathological processes, but gaining an idea of its reliability is still necessary for verification with an assessment of its sensitivity, specificity, and positive and negative predictive value. The telomere may be considered a putative predictive indicator of suicidal risk.},
}
RevDate: 2024-07-23
Structural variation in humans and our primate kin in the era of telomere-to-telomere genomes and pangenomics.
Current opinion in genetics & development, 87:102233 pii:S0959-437X(24)00082-0 [Epub ahead of print].
Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.
Additional Links: PMID-39042999
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@article {pmid39042999,
year = {2024},
author = {L Rocha, J and Lou, RN and Sudmant, PH},
title = {Structural variation in humans and our primate kin in the era of telomere-to-telomere genomes and pangenomics.},
journal = {Current opinion in genetics & development},
volume = {87},
number = {},
pages = {102233},
doi = {10.1016/j.gde.2024.102233},
pmid = {39042999},
issn = {1879-0380},
abstract = {Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.},
}
RevDate: 2024-07-23
Leukocyte telomere length in subjects with metabolic dysfunction-associated steatotic liver disease.
Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology pii:S1687-1979(24)00059-5 [Epub ahead of print].
BACKGROUND AND STUDY AIMS: This study aimed to examine the association between peripheral leukocyte telomere length and indicators of metabolic abnormalities in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) assessed by magnetic resonance imaging (MRI).
PATIENTS AND METHODS: This cross-sectional study included adults over 20 years with body mass index (BMI) of over >25 kg/m[2] and sonographic evidence of hepatic steatosis. The subjects were evaluated by clinical and biochemical variables, determination of hepatic fat fraction by MRI and relative peripheral leukocyte telomere length by quantitative real-time polymerase chain reaction.
RESULTS: Thirty-two subjects (22 men and 10 women) with MASLD were included, with a median age of 40 years, median BMI of 33.75 kg/m[2], median HFF 19 %, and median relative T/S ratio of 0.64. Subjects with relative T/S ratio below the median had significantly higher age, lower BMI, higher AST serum levels, higher GGT serum levels, lower serum ferritin levels, and higher FIB4 score. In a multivariable logistic regression model considering relative T/S ratio below or above the median only age was significantly associated with relative T/S ratio. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.
CONCLUSION: Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.
Additional Links: PMID-39043540
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PubMed:
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@article {pmid39043540,
year = {2024},
author = {Goncalves da Silva, D and Graciano da Silva, N and Amato, AA},
title = {Leukocyte telomere length in subjects with metabolic dysfunction-associated steatotic liver disease.},
journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajg.2024.06.005},
pmid = {39043540},
issn = {2090-2387},
abstract = {BACKGROUND AND STUDY AIMS: This study aimed to examine the association between peripheral leukocyte telomere length and indicators of metabolic abnormalities in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD) assessed by magnetic resonance imaging (MRI).
PATIENTS AND METHODS: This cross-sectional study included adults over 20 years with body mass index (BMI) of over >25 kg/m[2] and sonographic evidence of hepatic steatosis. The subjects were evaluated by clinical and biochemical variables, determination of hepatic fat fraction by MRI and relative peripheral leukocyte telomere length by quantitative real-time polymerase chain reaction.
RESULTS: Thirty-two subjects (22 men and 10 women) with MASLD were included, with a median age of 40 years, median BMI of 33.75 kg/m[2], median HFF 19 %, and median relative T/S ratio of 0.64. Subjects with relative T/S ratio below the median had significantly higher age, lower BMI, higher AST serum levels, higher GGT serum levels, lower serum ferritin levels, and higher FIB4 score. In a multivariable logistic regression model considering relative T/S ratio below or above the median only age was significantly associated with relative T/S ratio. Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.
CONCLUSION: Our findings suggest that age is the most important factor associated with telomere length among subjects with MASLD.},
}
RevDate: 2024-07-23
MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.
Journal of molecular medicine (Berlin, Germany) [Epub ahead of print].
MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.
Additional Links: PMID-39042290
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Citation:
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@article {pmid39042290,
year = {2024},
author = {Bortoletto, S and Nunes-Souza, E and Marchi, R and Ruthes, MO and Okano, LM and Tofolo, MV and Centa, A and Fonseca, AS and Rosolen, D and Cavalli, LR},
title = {MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {},
number = {},
pages = {},
pmid = {39042290},
issn = {1432-1440},
abstract = {MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.},
}
RevDate: 2024-07-22
SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML.
Genes & development pii:gad.351667.124 [Epub ahead of print].
The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether-and if so, how-SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.
Additional Links: PMID-39038850
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@article {pmid39038850,
year = {2024},
author = {Zhao, R and Xu, M and Yu, X and Wondisford, AR and Lackner, RM and Salsman, J and Dellaire, G and Chenoweth, DM and O'Sullivan, RJ and Zhao, X and Zhang, H},
title = {SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML.},
journal = {Genes & development},
volume = {},
number = {},
pages = {},
doi = {10.1101/gad.351667.124},
pmid = {39038850},
issn = {1549-5477},
abstract = {The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether-and if so, how-SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.},
}
RevDate: 2024-07-22
CmpDate: 2024-07-22
High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.
Hepatology communications, 8(8): pii:02009842-202408010-00009.
BACKGROUND: Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD).
METHODS: As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD.
RESULTS: This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel.
CONCLUSIONS: Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.
Additional Links: PMID-39037376
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@article {pmid39037376,
year = {2024},
author = {Coukos, A and Saglietti, C and Sempoux, C and Haubitz, M and Greuter, T and Mittaz-Crettol, L and Maurer, F and Mdawar-Bailly, E and Moradpour, D and Alberio, L and Good, JM and Baerlocher, GM and Fraga, M},
title = {High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.},
journal = {Hepatology communications},
volume = {8},
number = {8},
pages = {},
doi = {10.1097/HC9.0000000000000500},
pmid = {39037376},
issn = {2471-254X},
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; *Telomere Shortening/genetics ; Aged ; Adult ; Prevalence ; Telomere/genetics ; Hypertension, Portal/genetics ; In Situ Hybridization, Fluorescence ; Telomere-Binding Proteins/genetics ; Telomerase/genetics ; },
abstract = {BACKGROUND: Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD).
METHODS: As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD.
RESULTS: This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel.
CONCLUSIONS: Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Humans
Male
Female
Cross-Sectional Studies
Middle Aged
*Telomere Shortening/genetics
Aged
Adult
Prevalence
Telomere/genetics
Hypertension, Portal/genetics
In Situ Hybridization, Fluorescence
Telomere-Binding Proteins/genetics
Telomerase/genetics
RevDate: 2024-07-21
CmpDate: 2024-07-20
Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study.
BMC pregnancy and childbirth, 24(1):490.
BACKGROUND: Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.
METHODS: This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks' gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.
RESULTS: 156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).
CONCLUSION: Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.
Additional Links: PMID-39033276
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Citation:
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@article {pmid39033276,
year = {2024},
author = {Panelli, DM and Wang, X and Mayo, J and Wong, RJ and Hong, X and Becker, M and Aghaeepour, N and Druzin, ML and Zuckerman, BS and Stevenson, DK and Shaw DrPH, GM and Bianco, K},
title = {Association of pregnancy complications and postpartum maternal leukocyte telomeres in two diverse cohorts: a nested case-control study.},
journal = {BMC pregnancy and childbirth},
volume = {24},
number = {1},
pages = {490},
pmid = {39033276},
issn = {1471-2393},
support = {NIH K12HD103084/NH/NIH HHS/United States ; R35GM138353/GF/NIH HHS/United States ; },
mesh = {Humans ; Female ; Pregnancy ; Case-Control Studies ; Adult ; *Leukocytes ; *Postpartum Period ; *Pre-Eclampsia/blood ; *Premature Birth/epidemiology ; Pilot Projects ; Pregnancy Complications/blood ; Telomere ; Cohort Studies ; Urban Population/statistics & numerical data ; Telomere Shortening ; Young Adult ; },
abstract = {BACKGROUND: Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth.
METHODS: This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks' gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy.
RESULTS: 156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02).
CONCLUSION: Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Humans
Female
Pregnancy
Case-Control Studies
Adult
*Leukocytes
*Postpartum Period
*Pre-Eclampsia/blood
*Premature Birth/epidemiology
Pilot Projects
Pregnancy Complications/blood
Telomere
Cohort Studies
Urban Population/statistics & numerical data
Telomere Shortening
Young Adult
RevDate: 2024-07-20
Mode of delivery predicts postpartum maternal leukocyte telomere length.
European journal of obstetrics, gynecology, and reproductive biology, 300:224-229 pii:S0301-2115(24)00361-0 [Epub ahead of print].
BACKGROUND: Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging.
STUDY DESIGN: Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma).
RESULTS: Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction.
CONCLUSION: Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.
Additional Links: PMID-39032311
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PubMed:
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@article {pmid39032311,
year = {2024},
author = {Panelli, DM and Mayo, JA and Wong, RJ and Becker, M and Feyaerts, D and Marić, I and Wu, E and Gotlib, IH and Gaudillière, B and Aghaeepour, N and Druzin, ML and Stevenson, DK and Shaw, GM and Bianco, K},
title = {Mode of delivery predicts postpartum maternal leukocyte telomere length.},
journal = {European journal of obstetrics, gynecology, and reproductive biology},
volume = {300},
number = {},
pages = {224-229},
doi = {10.1016/j.ejogrb.2024.07.026},
pmid = {39032311},
issn = {1872-7654},
abstract = {BACKGROUND: Recent studies have suggested that pregnancy accelerates biologic aging, yet little is known about how biomarkers of aging are affected by events during the peripartum period. Given that immune shifts are known to occur following surgery, we explored the relation between mode of delivery and postpartum maternal leukocyte telomere length (LTL), a marker of biologic aging.
STUDY DESIGN: Postpartum maternal blood samples were obtained from a prospective cohort of term, singleton livebirths without hypertensive disorders or peripartum infections between 2012 and 2018. The primary outcome was postpartum LTLs from one blood sample drawn between postpartum week 1 and up to 6 months postpartum, measured from thawed frozen peripheral blood mononuclear cells using quantitative PCR in basepairs (bp). Multivariable linear regression models compared LTLs between vaginal versus cesarean births, adjusting for age, body mass index, and nulliparity as potential confounders. Analyses were conducted in two mutually exclusive groups: those with LTL measured postpartum week 1 and those measured up to 6 months postpartum. Secondarily, we compared multiomics by mode of delivery using machine-learning methods to evaluate whether other biologic changes occurred following cesarean. These included transcriptomics, metabolomics, microbiomics, immunomics, and proteomics (serum and plasma).
RESULTS: Of 67 included people, 50 (74.6 %) had vaginal and 17 (25.4 %) had cesarean births. LTLs were significantly shorter after cesarean in postpartum week 1 (5755.2 bp cesarean versus 6267.8 bp vaginal, p = 0.01) as well as in the later draws (5586.6 versus 5945.6 bp, p = 0.04). After adjusting for confounders, these differences persisted in both week 1 (adjusted beta -496.1, 95 % confidence interval [CI] -891.1, -101.1, p = 0.01) and beyond (adjusted beta -396.8; 95 % CI -727.2, -66.4. p = 0.02). Among the 15 participants who also had complete postpartum multiomics data available, there were predictive signatures of vaginal versus cesarean births in transcriptomics (cell-free [cf]RNA), metabolomics, microbiomics, and proteomics that did not persist after false discovery correction.
CONCLUSION: Maternal LTLs in postpartum week 1 were nearly 500 bp shorter following cesarean. This difference persisted several weeks postpartum, even though other markers of inflammation had normalized. Mode of delivery should be considered in any analyses of postpartum LTLs and further investigation into this phenomenon is warranted.},
}
RevDate: 2024-07-20
CmpDate: 2024-07-20
Loss of Chromosome Y in Neuroblastoma Is Associated With High-Risk Disease, 11q-Deletion, and Telomere Maintenance.
Genes, chromosomes & cancer, 63(7):e23260.
Neuroblastoma (NB) is a heterogeneous childhood cancer with a slightly higher incidence in boys than girls, with the reason for this gender disparity unknown. Given the growing evidence for the involvement of loss of the Y chromosome (LoY) in male diseases including cancer, we investigated Y chromosome status in NB. Male NB tumor samples from a Swedish cohort, analyzed using Cytoscan HD SNP-microarray, were selected. Seventy NB tumors were analyzed for aneuploidy of the Y chromosome, and these data were correlated with other genetic, biological, and clinical parameters. LoY was found in 21% of the male NB tumors and it was almost exclusively found in those with high-risk genomic profiles. Furthermore, LoY was associated with increased age at diagnosis and enriched in tumors with 11q-deletion and activated telomere maintenance mechanisms. In contrast, tumors with an MYCN-amplified genomic profile retained their Y chromosome. The understanding of LoY in cancer is limited, making it difficult to conclude whether LoY is a driving event in NB or function of increased genomic instability. Gene expression analysis of Y chromosome genes in male NB tumors showed low expression of certain genes correlating with worse overall survival. KDM5D, encoding a histone demethylase stands out as an interesting candidate for further studies. LoY has been shown to impact the epigenomic layer of autosomal loci in nonreproductive tissues, and KDM5D has been reported as downregulated and/or associated with poor survival in different malignancies. Further studies are needed to explore the mechanisms and functional consequences of LoY in NB.
Additional Links: PMID-39031441
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PubMed:
Citation:
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@article {pmid39031441,
year = {2024},
author = {Djos, A and Svensson, J and Gaarder, J and Umapathy, G and Nilsson, S and Ek, T and Vogt, H and Georgantzi, K and Öra, I and Träger, C and Kogner, P and Martinsson, T and Fransson, S},
title = {Loss of Chromosome Y in Neuroblastoma Is Associated With High-Risk Disease, 11q-Deletion, and Telomere Maintenance.},
journal = {Genes, chromosomes & cancer},
volume = {63},
number = {7},
pages = {e23260},
doi = {10.1002/gcc.23260},
pmid = {39031441},
issn = {1098-2264},
support = {TM 22-156; SF 18-99 18-099//Swedish Childhood Cancer Foundation/ ; PK PR2023-007//Swedish Childhood Cancer Foundation/ ; KP2020-0021//Swedish Childhood Cancer Foundation/ ; PROF2019-0001//Swedish Childhood Cancer Foundation/ ; TM 22-2359//Swedish Cancer Foundation/ ; PK 22-2492 Pj//Swedish Cancer Foundation/ ; ALFGBG-447171//Swedish state under the LUA/ALF agreement/ ; TM 521-2014-3031//Swedish Research Council/ ; TM/PK-RB13-0204//Swedish Foundation for Strategic Research/ ; },
mesh = {Humans ; *Neuroblastoma/genetics/pathology ; Male ; *Chromosomes, Human, Y/genetics ; *Chromosome Deletion ; *Chromosomes, Human, Pair 11/genetics ; Infant ; Child, Preschool ; Female ; Telomere Homeostasis/genetics ; Child ; Histone Demethylases/genetics ; Telomere/genetics ; N-Myc Proto-Oncogene Protein/genetics ; Sweden/epidemiology ; },
abstract = {Neuroblastoma (NB) is a heterogeneous childhood cancer with a slightly higher incidence in boys than girls, with the reason for this gender disparity unknown. Given the growing evidence for the involvement of loss of the Y chromosome (LoY) in male diseases including cancer, we investigated Y chromosome status in NB. Male NB tumor samples from a Swedish cohort, analyzed using Cytoscan HD SNP-microarray, were selected. Seventy NB tumors were analyzed for aneuploidy of the Y chromosome, and these data were correlated with other genetic, biological, and clinical parameters. LoY was found in 21% of the male NB tumors and it was almost exclusively found in those with high-risk genomic profiles. Furthermore, LoY was associated with increased age at diagnosis and enriched in tumors with 11q-deletion and activated telomere maintenance mechanisms. In contrast, tumors with an MYCN-amplified genomic profile retained their Y chromosome. The understanding of LoY in cancer is limited, making it difficult to conclude whether LoY is a driving event in NB or function of increased genomic instability. Gene expression analysis of Y chromosome genes in male NB tumors showed low expression of certain genes correlating with worse overall survival. KDM5D, encoding a histone demethylase stands out as an interesting candidate for further studies. LoY has been shown to impact the epigenomic layer of autosomal loci in nonreproductive tissues, and KDM5D has been reported as downregulated and/or associated with poor survival in different malignancies. Further studies are needed to explore the mechanisms and functional consequences of LoY in NB.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Humans
*Neuroblastoma/genetics/pathology
Male
*Chromosomes, Human, Y/genetics
*Chromosome Deletion
*Chromosomes, Human, Pair 11/genetics
Infant
Child, Preschool
Female
Telomere Homeostasis/genetics
Child
Histone Demethylases/genetics
Telomere/genetics
N-Myc Proto-Oncogene Protein/genetics
Sweden/epidemiology
RevDate: 2024-07-19
CmpDate: 2024-07-19
Telomere Elongation During Pre-Implantation Embryo Development.
Advances in anatomy, embryology, and cell biology, 238:121-129.
The primary mechanism of telomere elongation in mammals is reverse transcription by telomerase. An alternative (ALT) pathway elongates telomeres by homologous recombination in some cancer cells and during pre-implantation embryo development, when telomere length increases rapidly within a few cell cycles. The maternal and paternal telomeres in the zygote are genetically and epigenetically distinct, with differences in telomere length and in chromatin packaging. We discuss models for how these asymmetries may contribute to telomere regulation during the earliest embryonic cell cycles and suggest directions for future research.
Additional Links: PMID-39030357
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@article {pmid39030357,
year = {2024},
author = {Jeon, HJ and Levine, MT and Lampson, MA},
title = {Telomere Elongation During Pre-Implantation Embryo Development.},
journal = {Advances in anatomy, embryology, and cell biology},
volume = {238},
number = {},
pages = {121-129},
pmid = {39030357},
issn = {0301-5556},
mesh = {Animals ; *Embryonic Development/genetics ; *Telomere/metabolism ; Humans ; Telomere Homeostasis ; Telomerase/metabolism/genetics ; },
abstract = {The primary mechanism of telomere elongation in mammals is reverse transcription by telomerase. An alternative (ALT) pathway elongates telomeres by homologous recombination in some cancer cells and during pre-implantation embryo development, when telomere length increases rapidly within a few cell cycles. The maternal and paternal telomeres in the zygote are genetically and epigenetically distinct, with differences in telomere length and in chromatin packaging. We discuss models for how these asymmetries may contribute to telomere regulation during the earliest embryonic cell cycles and suggest directions for future research.},
}
MeSH Terms:
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Animals
*Embryonic Development/genetics
*Telomere/metabolism
Humans
Telomere Homeostasis
Telomerase/metabolism/genetics
RevDate: 2024-07-18
Is it possible that menopause is associated with telomere length? Findings of an integrative review.
Climacteric : the journal of the International Menopause Society [Epub ahead of print].
OBJECTIVE: Knowing the important repercussions of menopause for women's health and that female longevity can be better understood through studies based on aging biomarkers, studies on the relationship between menopause and telomere shortening may help to better understand this stage of life. This study aimed to analyze what research has been produced regarding the relationship between menopause and telomere length.
METHODS: This integrative literature review included searches in PubMed, CINAHL, LILACS, Web of Science and Scopus databases. Four studies were selected for the final sample.
RESULTS: The findings of these studies indicate that older age for menopause and longer reproductive life (difference between age at menopause and menarche) are associated with longer telomeres, that is, with longevity.
CONCLUSION: The relationship between menopause and telomere length is uncertain. The small number of studies included in this review, and the fact that the results indicate that the relationship between menopause and telomere length may be dependent on the stage of the menopause and race/ethnicity, suggest that additional research focusing on these variables should be carried out.
Additional Links: PMID-39023108
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@article {pmid39023108,
year = {2024},
author = {Bem, MMS and Paraizo-Horvath, CMS and Freitas, PS and Brito, TRP},
title = {Is it possible that menopause is associated with telomere length? Findings of an integrative review.},
journal = {Climacteric : the journal of the International Menopause Society},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/13697137.2024.2376193},
pmid = {39023108},
issn = {1473-0804},
abstract = {OBJECTIVE: Knowing the important repercussions of menopause for women's health and that female longevity can be better understood through studies based on aging biomarkers, studies on the relationship between menopause and telomere shortening may help to better understand this stage of life. This study aimed to analyze what research has been produced regarding the relationship between menopause and telomere length.
METHODS: This integrative literature review included searches in PubMed, CINAHL, LILACS, Web of Science and Scopus databases. Four studies were selected for the final sample.
RESULTS: The findings of these studies indicate that older age for menopause and longer reproductive life (difference between age at menopause and menarche) are associated with longer telomeres, that is, with longevity.
CONCLUSION: The relationship between menopause and telomere length is uncertain. The small number of studies included in this review, and the fact that the results indicate that the relationship between menopause and telomere length may be dependent on the stage of the menopause and race/ethnicity, suggest that additional research focusing on these variables should be carried out.},
}
RevDate: 2024-07-18
Investigating the structural and functional consequences of germline single nucleotide polymorphisms located in the genes of the alternative lengthening of telomere (ALT) pathway.
Heliyon, 10(12):e33110.
BACKGROUND: The Alternative Lengthening of Telomeres (ALT) pathway represents a non-canonical mechanism of telomere maintenance that operates independently of the conventional telomerase activity. The three biologically significant proteins, designated as SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), DAXX (Death domain-associated protein 6) and ATRX (alpha-thalassemia/mental retardation, X-linked) are associated with ALT in certain cancer types. The purpose of this study was to identify the most high-risk nsSNPs (non-synonymous Single Nucleotide Polymorphisms) within these three genes and assess their impacts on the structure and function of the proteins they encode.
METHODS: The reported genetic polymorphisms of SMARCAL1, DAXX and ATRX genes were retrieved from the Ensembl database. Later, various computational tools like PROVEAN, PolyPhen2, SNPs and GO, SNAP2, Predict-SNP, Panther and PMut were used to predict the most deleterious nsSNPs. MutPred was used to understand the underlying molecular reasons of those nsSNPs being deleterious, followed by prediction of Post Translational Modification Sites (PTMs) using ModPred. I-Mutant and MUpro were used to predict the effect of SNP on energy stability. Later, 3D clustering analysis was done using Mutation 3D server. Moreover, ConSurf was utilized to identify the conservation scores of wild-type amino acids. Additionally, the NCBI conserved domain search tool was employed to pinpoint conserved domains within these three proteins. Project-Hope helped for biophysical validation, followed by prediction of these genes' interaction and function by using GeneMANIA.
RESULT: Analysis on SMARCAL1 protein revealed that among 665 nsSNPs, four were identified as the most deleterious: L578S, T581S, P582A, and P582S. Similarly, within the DAXX protein, among a pool of 480 nsSNPs, P284S, R230C, and R230S were found out to be the most deleterious variants. In case of ATRX protein, V178D, R246C, and V277G, from the total of 1009 nsSNPs, were predicted to be the most deleterious. All these nsSNPs were found to occur at residue positions that are 100 % conserved within protein domains and were predicted to be most damaging from both structural and functional perspectives and highly destabilizing to their corresponding proteins.
CONCLUSION: Computational investigation on the 3 proteins-SMARCAL1, DAXX and ATRX through different bioinformatics analysis tools concludes that the identified high risk nsSNPs of these proteins are pathogenic SNPs. These variants potentially exert functional and structural influences, thus making them valuable candidates for future genetic studies.
Additional Links: PMID-39021990
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Citation:
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@article {pmid39021990,
year = {2024},
author = {Nila, NN and Mahmud, Z and Paul, A and Rahman, T and Hossain Howlader, MZ and Hosen, MI},
title = {Investigating the structural and functional consequences of germline single nucleotide polymorphisms located in the genes of the alternative lengthening of telomere (ALT) pathway.},
journal = {Heliyon},
volume = {10},
number = {12},
pages = {e33110},
pmid = {39021990},
issn = {2405-8440},
abstract = {BACKGROUND: The Alternative Lengthening of Telomeres (ALT) pathway represents a non-canonical mechanism of telomere maintenance that operates independently of the conventional telomerase activity. The three biologically significant proteins, designated as SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1), DAXX (Death domain-associated protein 6) and ATRX (alpha-thalassemia/mental retardation, X-linked) are associated with ALT in certain cancer types. The purpose of this study was to identify the most high-risk nsSNPs (non-synonymous Single Nucleotide Polymorphisms) within these three genes and assess their impacts on the structure and function of the proteins they encode.
METHODS: The reported genetic polymorphisms of SMARCAL1, DAXX and ATRX genes were retrieved from the Ensembl database. Later, various computational tools like PROVEAN, PolyPhen2, SNPs and GO, SNAP2, Predict-SNP, Panther and PMut were used to predict the most deleterious nsSNPs. MutPred was used to understand the underlying molecular reasons of those nsSNPs being deleterious, followed by prediction of Post Translational Modification Sites (PTMs) using ModPred. I-Mutant and MUpro were used to predict the effect of SNP on energy stability. Later, 3D clustering analysis was done using Mutation 3D server. Moreover, ConSurf was utilized to identify the conservation scores of wild-type amino acids. Additionally, the NCBI conserved domain search tool was employed to pinpoint conserved domains within these three proteins. Project-Hope helped for biophysical validation, followed by prediction of these genes' interaction and function by using GeneMANIA.
RESULT: Analysis on SMARCAL1 protein revealed that among 665 nsSNPs, four were identified as the most deleterious: L578S, T581S, P582A, and P582S. Similarly, within the DAXX protein, among a pool of 480 nsSNPs, P284S, R230C, and R230S were found out to be the most deleterious variants. In case of ATRX protein, V178D, R246C, and V277G, from the total of 1009 nsSNPs, were predicted to be the most deleterious. All these nsSNPs were found to occur at residue positions that are 100 % conserved within protein domains and were predicted to be most damaging from both structural and functional perspectives and highly destabilizing to their corresponding proteins.
CONCLUSION: Computational investigation on the 3 proteins-SMARCAL1, DAXX and ATRX through different bioinformatics analysis tools concludes that the identified high risk nsSNPs of these proteins are pathogenic SNPs. These variants potentially exert functional and structural influences, thus making them valuable candidates for future genetic studies.},
}
RevDate: 2024-07-17
Shorter Telomere Length Is Associated With Older Age, Poor Sleep Hygiene, and Orthopedic Injury, but Not Mild Traumatic Brain Injury, in a Cohort of Canadian Children.
The Journal of head trauma rehabilitation [Epub ahead of print].
BACKGROUND: Predicting recovery following pediatric mild traumatic brain injury (mTBI) remains challenging. The identification of objective biomarkers for prognostic purposes could improve clinical outcomes. Telomere length (TL) has previously been used as a prognostic marker of cellular health in the context of mTBI and other neurobiological conditions. While psychosocial and environmental factors are associated with recovery outcomes following pediatric mTBI, the relationship between these factors and TL has not been investigated. This study sought to examine the relationships between TL and psychosocial and environmental factors, in a cohort of Canadian children with mTBI or orthopedic injury (OI).
METHODS: Saliva was collected at a postacute (median 7 days) timepoint following injury to assess TL from a prospective longitudinal cohort of children aged 8 to 17 years with either mTBI (n = 202) or OI (n = 90), recruited from 3 Canadian sites. Questionnaires regarding psychosocial and environmental factors were obtained at a postacute follow-up visit and injury outcomes were assessed at a 3-month visit. Univariable associations between TL and psychosocial, environmental, and outcome variables were assessed using Spearman's correlation. Further adjusted analyses of these associations were performed by including injury group, age, sex, and site as covariates in multivariable generalized linear models with a Poisson family, log link function, and robust variance estimates.
RESULTS: After adjusting for age, sex, and site, TL in participants with OI was 7% shorter than those with mTBI (adjusted mean ratio = 0.93; 95% confidence interval, 0.89-0.98; P = .003). As expected, increasing age was negatively associated with TL (Spearman's r = -0.14, P = .016). Sleep hygiene at 3 months was positively associated with TL (adjusted mean ratio = 1.010; 95% confidence interval, 1.001-1.020; P = .039).
CONCLUSION: The relationships between TL and psychosocial and environmental factors in pediatric mTBI and OI are complex. TL may provide information regarding sleep quality in children recovering from mTBI or OI; however, further investigation into TL biomarker validity should employ a noninjured comparison group.
Additional Links: PMID-39019487
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Citation:
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@article {pmid39019487,
year = {2024},
author = {Salberg, S and Smith, MJ and Lamont, R and Chen, Z and Beauchamp, MH and Craig, W and Doan, Q and Gravel, J and Zemek, R and Lannin, NA and Yeates, KO and Mychasiuk, R},
title = {Shorter Telomere Length Is Associated With Older Age, Poor Sleep Hygiene, and Orthopedic Injury, but Not Mild Traumatic Brain Injury, in a Cohort of Canadian Children.},
journal = {The Journal of head trauma rehabilitation},
volume = {},
number = {},
pages = {},
pmid = {39019487},
issn = {1550-509X},
abstract = {BACKGROUND: Predicting recovery following pediatric mild traumatic brain injury (mTBI) remains challenging. The identification of objective biomarkers for prognostic purposes could improve clinical outcomes. Telomere length (TL) has previously been used as a prognostic marker of cellular health in the context of mTBI and other neurobiological conditions. While psychosocial and environmental factors are associated with recovery outcomes following pediatric mTBI, the relationship between these factors and TL has not been investigated. This study sought to examine the relationships between TL and psychosocial and environmental factors, in a cohort of Canadian children with mTBI or orthopedic injury (OI).
METHODS: Saliva was collected at a postacute (median 7 days) timepoint following injury to assess TL from a prospective longitudinal cohort of children aged 8 to 17 years with either mTBI (n = 202) or OI (n = 90), recruited from 3 Canadian sites. Questionnaires regarding psychosocial and environmental factors were obtained at a postacute follow-up visit and injury outcomes were assessed at a 3-month visit. Univariable associations between TL and psychosocial, environmental, and outcome variables were assessed using Spearman's correlation. Further adjusted analyses of these associations were performed by including injury group, age, sex, and site as covariates in multivariable generalized linear models with a Poisson family, log link function, and robust variance estimates.
RESULTS: After adjusting for age, sex, and site, TL in participants with OI was 7% shorter than those with mTBI (adjusted mean ratio = 0.93; 95% confidence interval, 0.89-0.98; P = .003). As expected, increasing age was negatively associated with TL (Spearman's r = -0.14, P = .016). Sleep hygiene at 3 months was positively associated with TL (adjusted mean ratio = 1.010; 95% confidence interval, 1.001-1.020; P = .039).
CONCLUSION: The relationships between TL and psychosocial and environmental factors in pediatric mTBI and OI are complex. TL may provide information regarding sleep quality in children recovering from mTBI or OI; however, further investigation into TL biomarker validity should employ a noninjured comparison group.},
}
RevDate: 2024-07-16
Malaria endemicity linked to shorter telomeres in leukocytes.
Trends in parasitology pii:S1471-4922(24)00176-4 [Epub ahead of print].
Leukocyte telomere length is a highly polygenic trait that has been associated with a complex range of lifestyle factors and disease risk. McQuillan et al.'s results comparing telomere length to malaria incidence rates suggest that infections may be another important factor, possibly through permanent shortening of telomeres in hematopoietic progenitor cells.
Additional Links: PMID-39013662
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PubMed:
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@article {pmid39013662,
year = {2024},
author = {Band, G and Leffler, EM},
title = {Malaria endemicity linked to shorter telomeres in leukocytes.},
journal = {Trends in parasitology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pt.2024.06.017},
pmid = {39013662},
issn = {1471-5007},
abstract = {Leukocyte telomere length is a highly polygenic trait that has been associated with a complex range of lifestyle factors and disease risk. McQuillan et al.'s results comparing telomere length to malaria incidence rates suggest that infections may be another important factor, possibly through permanent shortening of telomeres in hematopoietic progenitor cells.},
}
RevDate: 2024-07-16
Physical Performance and Telomere Length in Older Adults.
Archives of medical research, 55(6):103046 pii:S0188-4409(24)00098-5 [Epub ahead of print].
BACKGROUND: The aging population prompts studying risk factors and markers to predict healthy aging. Telomere length is a promising candidate for assessing various age-related traits.
AIM OF THE STUDY: To investigate the association between physical performance and telomere length.
METHODS: We enrolled 323 older Mexican adults from the "Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults" affiliated with the Instituto Mexicano del Seguro Social and assessed their physical performance using the Short Physical Performance Battery, dividing participants into low (≤7) and high (>7) groups. Absolute telomere length was determined by qPCR, and individuals were classified into short (≤4.22 kb) and long (>4.22 kb) groups. We calculated the mean and adjusted mean, considering sex and age, among others, with 95% CI. We estimated the effect size between physical performance and telomere length using Cohen's d for unequal group sizes and calculated the odds ratio for physical performance based on telomere length.
RESULTS: Participants with low physical performance had significantly shorter telomeres (mean 4.14.44.7 kb, adjusted mean 3.54.04.5 kb, p <0.001), while those with high physical performance exhibited longer telomeres (mean 5.55.75.9 kb, adjusted mean 4.75.35.8 kb, p <0.001), with a medium-to-high telomere length effect size (d = 0.762). The odds of low physical activity increased 2.13.66.1-fold per kb of telomere attrition (adjOR 1.73.36.3, p <0.001).
CONCLUSION: Decreased physical function is associated with shorter telomere length. Absolute telomere length presents a promising biomarker for distinguishing between healthy and unhealthy aging, warranting further investigation.
Additional Links: PMID-39013263
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PubMed:
Citation:
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@article {pmid39013263,
year = {2024},
author = {Martínez-Ezquerro, JD and Ortiz-Ramírez, M and García-delaTorre, P and González-Covarrubias, V and Sánchez-García, S},
title = {Physical Performance and Telomere Length in Older Adults.},
journal = {Archives of medical research},
volume = {55},
number = {6},
pages = {103046},
doi = {10.1016/j.arcmed.2024.103046},
pmid = {39013263},
issn = {1873-5487},
abstract = {BACKGROUND: The aging population prompts studying risk factors and markers to predict healthy aging. Telomere length is a promising candidate for assessing various age-related traits.
AIM OF THE STUDY: To investigate the association between physical performance and telomere length.
METHODS: We enrolled 323 older Mexican adults from the "Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults" affiliated with the Instituto Mexicano del Seguro Social and assessed their physical performance using the Short Physical Performance Battery, dividing participants into low (≤7) and high (>7) groups. Absolute telomere length was determined by qPCR, and individuals were classified into short (≤4.22 kb) and long (>4.22 kb) groups. We calculated the mean and adjusted mean, considering sex and age, among others, with 95% CI. We estimated the effect size between physical performance and telomere length using Cohen's d for unequal group sizes and calculated the odds ratio for physical performance based on telomere length.
RESULTS: Participants with low physical performance had significantly shorter telomeres (mean 4.14.44.7 kb, adjusted mean 3.54.04.5 kb, p <0.001), while those with high physical performance exhibited longer telomeres (mean 5.55.75.9 kb, adjusted mean 4.75.35.8 kb, p <0.001), with a medium-to-high telomere length effect size (d = 0.762). The odds of low physical activity increased 2.13.66.1-fold per kb of telomere attrition (adjOR 1.73.36.3, p <0.001).
CONCLUSION: Decreased physical function is associated with shorter telomere length. Absolute telomere length presents a promising biomarker for distinguishing between healthy and unhealthy aging, warranting further investigation.},
}
RevDate: 2024-07-16
CmpDate: 2024-07-16
TRF1 and TRF2: pioneering targets in telomere-based cancer therapy.
Journal of cancer research and clinical oncology, 150(7):353.
This article presents an in-depth exploration of the roles of Telomere Repeat-binding Factors 1 and 2 (TRF1 and TRF2), and the shelterin complex, in the context of cancer biology. It emphasizes their emerging significance as potential biomarkers and targets for therapeutic intervention. Central to the shelterin complex, TRF1 and TRF2 are crucial in maintaining telomere integrity and genomic stability, their dysregulation often being a hallmark of cancerous cells. The article delves into the diagnostic and prognostic capabilities of TRF1 and TRF2 across various cancer types, highlighting their sensitivity and specificity. Furthermore, it reviews current strides in drug discovery targeting the shelterin complex, detailing specific compounds and their modes of action. The review candidly addresses the challenges in developing therapies aimed at the shelterin complex, including drug resistance, off-target effects, and issues in drug delivery. By synthesizing recent research findings, the article sheds light on the intricate relationship between telomere biology and cancer development. It underscores the urgency for continued research to navigate the existing challenges and fully leverage the therapeutic potential of TRF1, TRF2, and the shelterin complex in the realm of cancer treatment.
Additional Links: PMID-39012375
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@article {pmid39012375,
year = {2024},
author = {Kallingal, A and Krzemieniecki, R and Maciejewska, N and Brankiewicz-Kopcińska, W and Baginski, M},
title = {TRF1 and TRF2: pioneering targets in telomere-based cancer therapy.},
journal = {Journal of cancer research and clinical oncology},
volume = {150},
number = {7},
pages = {353},
pmid = {39012375},
issn = {1432-1335},
mesh = {Humans ; *Neoplasms/genetics/drug therapy/metabolism/therapy ; *Telomeric Repeat Binding Protein 2/metabolism/genetics ; *Telomeric Repeat Binding Protein 1/metabolism/genetics ; *Telomere/metabolism ; Molecular Targeted Therapy/methods ; Antineoplastic Agents/therapeutic use/pharmacology ; Shelterin Complex ; Telomere-Binding Proteins ; },
abstract = {This article presents an in-depth exploration of the roles of Telomere Repeat-binding Factors 1 and 2 (TRF1 and TRF2), and the shelterin complex, in the context of cancer biology. It emphasizes their emerging significance as potential biomarkers and targets for therapeutic intervention. Central to the shelterin complex, TRF1 and TRF2 are crucial in maintaining telomere integrity and genomic stability, their dysregulation often being a hallmark of cancerous cells. The article delves into the diagnostic and prognostic capabilities of TRF1 and TRF2 across various cancer types, highlighting their sensitivity and specificity. Furthermore, it reviews current strides in drug discovery targeting the shelterin complex, detailing specific compounds and their modes of action. The review candidly addresses the challenges in developing therapies aimed at the shelterin complex, including drug resistance, off-target effects, and issues in drug delivery. By synthesizing recent research findings, the article sheds light on the intricate relationship between telomere biology and cancer development. It underscores the urgency for continued research to navigate the existing challenges and fully leverage the therapeutic potential of TRF1, TRF2, and the shelterin complex in the realm of cancer treatment.},
}
MeSH Terms:
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Humans
*Neoplasms/genetics/drug therapy/metabolism/therapy
*Telomeric Repeat Binding Protein 2/metabolism/genetics
*Telomeric Repeat Binding Protein 1/metabolism/genetics
*Telomere/metabolism
Molecular Targeted Therapy/methods
Antineoplastic Agents/therapeutic use/pharmacology
Shelterin Complex
Telomere-Binding Proteins
RevDate: 2024-07-15
Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis.
Journal of ovarian research, 17(1):146.
BACKGROUND: The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis.
METHODS: Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction.
RESULTS: Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880-1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970-1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350-1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983-1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671-1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919-1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644-1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137-1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results.
CONCLUSION: The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.
Additional Links: PMID-39010148
PubMed:
Citation:
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@article {pmid39010148,
year = {2024},
author = {Yang, Q and Zhang, J and Fan, Z},
title = {Causal association between telomere length and female reproductive endocrine diseases: a univariable and multivariable Mendelian randomization analysis.},
journal = {Journal of ovarian research},
volume = {17},
number = {1},
pages = {146},
pmid = {39010148},
issn = {1757-2215},
abstract = {BACKGROUND: The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis.
METHODS: Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction.
RESULTS: Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880-1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970-1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350-1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983-1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671-1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919-1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644-1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137-1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results.
CONCLUSION: The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future.},
}
RevDate: 2024-07-15
Profiling Tel1 Signaling Reveals a Non-Canonical Motif Targeting DNA Repair and Telomere Control Machineries.
bioRxiv : the preprint server for biology pii:2024.07.03.601872.
The stability of the genome relies on Phosphatidyl Inositol 3-Kinase-related Kinases (PIKKs) that sense DNA damage and trigger elaborate downstream signaling responses. In S. cerevisiae , the Tel1 kinase (ortholog of human ATM) is activated at DNA double strand breaks (DSBs) and short telomeres. Despite the well-established roles of Tel1 in the control of telomere maintenance, suppression of chromosomal rearrangements, activation of cell cycle checkpoints, and repair of DSBs, the substrates through which Tel1 controls these processes remain incompletely understood. Here we performed an in depth phosphoproteomic screen for Tel1-dependent phosphorylation events. To achieve maximal coverage of the phosphoproteome, we developed a scaled-up approach that accommodates large amounts of protein extracts and chromatographic fractions. Compared to previous reports, we expanded the number of detected Tel1-dependent phosphorylation events by over 10-fold. Surprisingly, in addition to the identification of phosphorylation sites featuring the canonical motif for Tel1 phosphorylation (S/T-Q), the results revealed a novel motif (D/E-S/T) highly prevalent and enriched in the set of Tel1-dependent events. This motif is unique to Tel1 signaling and not shared with the Mec1 kinase, providing clues to how Tel1 plays specialized roles in DNA repair and telomere length control. Overall, these findings define a Tel1-signaling network targeting numerous proteins involved in DNA repair, chromatin regulation, and telomere maintenance that represents a framework for dissecting the molecular mechanisms of Tel1 action.
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@article {pmid39005478,
year = {2024},
author = {Comstock, W and Sanford, E and Navarro, M and Smolka, MB},
title = {Profiling Tel1 Signaling Reveals a Non-Canonical Motif Targeting DNA Repair and Telomere Control Machineries.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.03.601872},
pmid = {39005478},
issn = {2692-8205},
abstract = {The stability of the genome relies on Phosphatidyl Inositol 3-Kinase-related Kinases (PIKKs) that sense DNA damage and trigger elaborate downstream signaling responses. In S. cerevisiae , the Tel1 kinase (ortholog of human ATM) is activated at DNA double strand breaks (DSBs) and short telomeres. Despite the well-established roles of Tel1 in the control of telomere maintenance, suppression of chromosomal rearrangements, activation of cell cycle checkpoints, and repair of DSBs, the substrates through which Tel1 controls these processes remain incompletely understood. Here we performed an in depth phosphoproteomic screen for Tel1-dependent phosphorylation events. To achieve maximal coverage of the phosphoproteome, we developed a scaled-up approach that accommodates large amounts of protein extracts and chromatographic fractions. Compared to previous reports, we expanded the number of detected Tel1-dependent phosphorylation events by over 10-fold. Surprisingly, in addition to the identification of phosphorylation sites featuring the canonical motif for Tel1 phosphorylation (S/T-Q), the results revealed a novel motif (D/E-S/T) highly prevalent and enriched in the set of Tel1-dependent events. This motif is unique to Tel1 signaling and not shared with the Mec1 kinase, providing clues to how Tel1 plays specialized roles in DNA repair and telomere length control. Overall, these findings define a Tel1-signaling network targeting numerous proteins involved in DNA repair, chromatin regulation, and telomere maintenance that represents a framework for dissecting the molecular mechanisms of Tel1 action.},
}
RevDate: 2024-07-13
Allogeneic hematopoietic cell transplant for bone marrow failure or myelodysplastic syndrome in dyskeratosis congenita/telomere biology disorders: Single-center single-arm open-label trial of reduced intensity conditioning without radiation.
Transplantation and cellular therapy pii:S2666-6367(24)00530-X [Epub ahead of print].
BACKGROUND: Dyskeratosis congenita/Telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field.
OBJECTIVES/STUDY DESIGN: We report prospectively collected standard alloHCT outcomes from a single-center single-arm open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC) including alemtuzumab 1mg/kg, fludarabine 200 mg/m[2], and cyclophosphamide 50 mg/kg. A previous single-arm open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 centigray of total body irradiation (TBI), served as a control cohort.
RESULTS: The Non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared to the control TBI cohort which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (Non-TBI) compared to 2.6 (TBI) x 10[6]/kg (p=0.02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0 and 10% (Non-TBI) and 8 and 17% (TBI), respectively (acute, p=0.36; chronic, p=0.72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (Non-TBI cohort). The Non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (Non-TBI) and 75% (TBI; p=0.78). MDS as an indication for alloHCT was uncommon, but overall associated with poor outcomes. There were 3 MDS patients in the Non-TBI cohort: 1 relapsed and died at day+387; 1 relapsed at day+500 and is alive 5.5 years later following salvage with a 2[nd] alloHCT; 1 relapsed at day+1093 and is alive at day +100 after a 2[nd] alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day+827 from a bacterial infection in the setting of immune mediated cytopenia.
CONCLUSION: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival, but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.
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@article {pmid39002862,
year = {2024},
author = {Dimitrov, M and Merkle, S and Cao, Q and Tryon, RK and Vercellotti, GM and Holtan, SG and Kao, RL and Srikanthan, M and Terezakis, SA and Tolar, J and Ebens, CL},
title = {Allogeneic hematopoietic cell transplant for bone marrow failure or myelodysplastic syndrome in dyskeratosis congenita/telomere biology disorders: Single-center single-arm open-label trial of reduced intensity conditioning without radiation.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.07.007},
pmid = {39002862},
issn = {2666-6367},
abstract = {BACKGROUND: Dyskeratosis congenita/Telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field.
OBJECTIVES/STUDY DESIGN: We report prospectively collected standard alloHCT outcomes from a single-center single-arm open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC) including alemtuzumab 1mg/kg, fludarabine 200 mg/m[2], and cyclophosphamide 50 mg/kg. A previous single-arm open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 centigray of total body irradiation (TBI), served as a control cohort.
RESULTS: The Non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared to the control TBI cohort which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (Non-TBI) compared to 2.6 (TBI) x 10[6]/kg (p=0.02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0 and 10% (Non-TBI) and 8 and 17% (TBI), respectively (acute, p=0.36; chronic, p=0.72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (Non-TBI cohort). The Non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (Non-TBI) and 75% (TBI; p=0.78). MDS as an indication for alloHCT was uncommon, but overall associated with poor outcomes. There were 3 MDS patients in the Non-TBI cohort: 1 relapsed and died at day+387; 1 relapsed at day+500 and is alive 5.5 years later following salvage with a 2[nd] alloHCT; 1 relapsed at day+1093 and is alive at day +100 after a 2[nd] alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day+827 from a bacterial infection in the setting of immune mediated cytopenia.
CONCLUSION: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival, but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.},
}
RevDate: 2024-07-13
Understanding seasonal telomere length dynamics in hibernating species.
Journal of thermal biology, 123:103913 pii:S0306-4565(24)00131-1 [Epub ahead of print].
Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.
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@article {pmid39002254,
year = {2024},
author = {Redon, L and Constant, T and Smith, S and Habold, C and Giroud, S},
title = {Understanding seasonal telomere length dynamics in hibernating species.},
journal = {Journal of thermal biology},
volume = {123},
number = {},
pages = {103913},
doi = {10.1016/j.jtherbio.2024.103913},
pmid = {39002254},
issn = {0306-4565},
abstract = {Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.},
}
RevDate: 2024-07-13
Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.
Biogerontology [Epub ahead of print].
Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging.
Additional Links: PMID-39001954
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@article {pmid39001954,
year = {2024},
author = {Boccardi, V and Cari, L and Bastiani, P and Scamosci, M and Cecchetti, R and Nocentini, G and Mecocci, P},
title = {Aberrant telomeric structures and serum markers of telomere dysfunction in healthy aging: a preliminary study.},
journal = {Biogerontology},
volume = {},
number = {},
pages = {},
pmid = {39001954},
issn = {1573-6768},
abstract = {Telomeres undergo a progressive shortening process as individuals age, and it has been proposed that severely shortened and dysfunctional telomeres play a role in the aging process and the onset of age-related diseases in human beings. An emerging body of evidence indicates that the shortening of telomeres in cultured human cells is also influenced by other replication defects occurring within telomeric repeats. These abnormalities can be detected on metaphase chromosomes. Recent studies have also identified a set of serological markers for telomere dysfunction and DNA damage (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase). With this study, the correlation between telomere abnormalities (by FISH) and these biomarkers as measured in blood serum (by ELISA) from a cohort of 22 healthy subjects at different ages (range 26-101 years) was analyzed. A strong positive correlation between aging and the presence of aberrant telomere structures, sister telomere loss (STL), and sister telomere chromatid fusions (STCF) was detected. When serum markers of telomere dysfunction were correlated with telomere abnormalities, we found that stathmin correlated with total aberrant telomeres structures (r = 0.431, p = 0.0453) and STCF (r = 0.533, p = 0.0107). These findings suggest that serum stathmin can be considered an easy-to-get marker of telomere dysfunction and may serve as valuable indicators of aging.},
}
RevDate: 2024-07-13
Telomere Length in Adolescent and Young Adult Survivors of Childhood Cancer.
Cancers, 16(13): pii:cancers16132344.
We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not (p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not (p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs (p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL (p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients.
Additional Links: PMID-39001406
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@article {pmid39001406,
year = {2024},
author = {Park, M and Lee, DE and Hong, Y and Suh, JK and Lee, JA and Kim, M and Park, HJ},
title = {Telomere Length in Adolescent and Young Adult Survivors of Childhood Cancer.},
journal = {Cancers},
volume = {16},
number = {13},
pages = {},
doi = {10.3390/cancers16132344},
pmid = {39001406},
issn = {2072-6694},
support = {2022-0195//National Cancer Center/Republic of Korea ; },
abstract = {We examined the leukocyte relative telomere length (RTL) in Korean adolescent and young adult (AYA) survivors of childhood cancer and evaluated the association of leukocyte RTL with multiple factors, including malignancy type, cancer treatment, age, and chronic health conditions (CHCs). Eighty-eight AYA survivors of childhood cancer with a median follow-up period of 73 months were recruited. RTL in pediatric cancer survivors was not significantly shorter than the predicted value for age-matched references. Neither age at diagnosis nor duration of therapy influenced the RTL. Among the 43 patients with hematologic malignancies, those who underwent allogeneic hematopoietic stem cell transplantation (HSCT) showed a significant shortening of the RTL compared with those who did not (p = 0.039). Among the 15 patients who underwent allogeneic HSCT, those who developed acute graft-versus-host disease (GVHD) of grade II or higher had significantly shorter RTL than those who did not (p = 0.012). Patients with grade II CHCs had significantly shorter RTL than those without CHCs or with grade I CHCs (p = 0.001). Survivors with ≥2 CHCs also exhibited shorter RTL (p = 0.027). Overall, pediatric cancer survivors had similar telomere lengths compared to age-matched references. HSCT recipients and patients with severe or multiple CHCs had shorter telomeres. GVHD augmented telomere attrition in HSCT recipients.},
}
RevDate: 2024-07-12
Adult telomere length is positively correlated with survival and lifetime reproductive success in a wild passerine.
Molecular ecology [Epub ahead of print].
Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short-term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length-survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics.
Additional Links: PMID-38993011
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@article {pmid38993011,
year = {2024},
author = {Chik, HYJ and Mannarelli, ME and Dos Remedios, N and Simons, MJP and Burke, T and Schroeder, J and Dugdale, HL},
title = {Adult telomere length is positively correlated with survival and lifetime reproductive success in a wild passerine.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {e17455},
doi = {10.1111/mec.17455},
pmid = {38993011},
issn = {1365-294X},
support = {PCIG12-GA-2012-333096/ERC_/European Research Council/International ; NE/J024567/1//Natural Environment Research Council/ ; },
abstract = {Explaining variation in individual fitness is a key goal in evolutionary biology. Recently, telomeres, repeating DNA sequences capping chromosome ends, have gained attention as a biomarker for body state, physiological costs, and senescence. Existing research has provided mixed evidence for whether telomere length correlates with fitness, including survival and reproductive output. Moreover, few studies have examined how the rate of change in telomere length correlates with fitness in wild populations. Here, we intensively monitored an insular population of house sparrows, and collected longitudinal telomere and life history data (16 years, 1225 individuals). We tested whether telomere length and its rate of change predict fitness measures, namely survival, lifespan and annual and lifetime reproductive effort and success. Telomere length positively predicted short-term survival, independent of age, but did not predict lifespan, suggesting either a diminishing telomere length-survival correlation with age or other extrinsic factors of mortality. The positive association of telomere length with survival translated into reproductive benefits, as birds with longer telomeres produced more genetic recruits, hatchlings and reared more fledglings over their lifetime. In contrast, there was no association between telomere dynamics and annual reproductive output, suggesting telomere dynamics might not reflect the costs of reproduction in this population, potentially masked by variation in individual quality. The rate of change of telomere length did not correlate with neither lifespan nor lifetime reproductive success. Our results provide further evidence that telomere length correlates with fitness, and contribute to our understanding of the selection on, and evolution of, telomere dynamics.},
}
RevDate: 2024-07-10
Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.
Cell communication and signaling : CCS, 22(1):357.
BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence.
METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155[-/-] mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization.
RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16[INK4A] expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16[INK4A]/p21expression and senescence-associated β-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs.
CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.
Additional Links: PMID-38987851
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@article {pmid38987851,
year = {2024},
author = {Yin, Q and Tang, TT and Lu, XY and Ni, WJ and Yin, D and Zhang, YL and Jiang, W and Zhang, Y and Li, ZL and Wen, Y and Gan, WH and Zhang, AQ and Lv, LL and Wang, B and Liu, BC},
title = {Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.},
journal = {Cell communication and signaling : CCS},
volume = {22},
number = {1},
pages = {357},
pmid = {38987851},
issn = {1478-811X},
support = {82070735;82030024;81720108007//National Natural Science Foundation of China/ ; 82070735;82030024;81720108007//National Natural Science Foundation of China/ ; 2018YFC130046, 2018YFC1314000//National Key Research Programme of Ministry of Science and Technology/ ; },
abstract = {BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence.
METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155[-/-] mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization.
RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16[INK4A] expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16[INK4A]/p21expression and senescence-associated β-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs.
CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.},
}
RevDate: 2024-07-09
Structure analysis of the telomere resolvase from the Lyme disease spirochete Borrelia garinii reveals functional divergence of its C-terminal domain.
Nucleic acids research pii:7709540 [Epub ahead of print].
Borrelia spirochetes are the causative agents of Lyme disease and relapsing fever, two of the most common tick-borne illnesses. A characteristic feature of these spirochetes is their highly segmented genomes which consists of a linear chromosome and a mixture of up to approximately 24 linear and circular extrachromosomal plasmids. The complexity of this genomic arrangement requires multiple strategies for efficient replication and partitioning during cell division, including the generation of hairpin ends found on linear replicons mediated by the essential enzyme ResT, a telomere resolvase. Using an integrative structural biology approach employing advanced modelling, circular dichroism, X-ray crystallography and small-angle X-ray scattering, we have generated high resolution structural data on ResT from B. garinii. Our data provides the first high-resolution structures of ResT from Borrelia spirochetes and revealed active site positioning in the catalytic domain. We also demonstrate that the C-terminal domain of ResT is required for both transesterification steps of telomere resolution, and is a requirement for DNA binding, distinguishing ResT from other telomere resolvases from phage and bacteria. These results advance our understanding of the molecular function of this essential enzyme involved in genome maintenance in Borrelia pathogens.
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@article {pmid38979576,
year = {2024},
author = {Semper, C and Watanabe, N and Karimullina, E and Patel, DT and Di Leo, R and Castellanos, M and Patel, DH and Chaconas, G and Savchenko, A},
title = {Structure analysis of the telomere resolvase from the Lyme disease spirochete Borrelia garinii reveals functional divergence of its C-terminal domain.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae580},
pmid = {38979576},
issn = {1362-4962},
support = {//National Institute of Allergy and Infectious Diseases/ ; HHSN272201700060C/NH/NIH HHS/United States ; /HH/HHS/United States ; PJT-153336/CAPMC/CIHR/Canada ; },
abstract = {Borrelia spirochetes are the causative agents of Lyme disease and relapsing fever, two of the most common tick-borne illnesses. A characteristic feature of these spirochetes is their highly segmented genomes which consists of a linear chromosome and a mixture of up to approximately 24 linear and circular extrachromosomal plasmids. The complexity of this genomic arrangement requires multiple strategies for efficient replication and partitioning during cell division, including the generation of hairpin ends found on linear replicons mediated by the essential enzyme ResT, a telomere resolvase. Using an integrative structural biology approach employing advanced modelling, circular dichroism, X-ray crystallography and small-angle X-ray scattering, we have generated high resolution structural data on ResT from B. garinii. Our data provides the first high-resolution structures of ResT from Borrelia spirochetes and revealed active site positioning in the catalytic domain. We also demonstrate that the C-terminal domain of ResT is required for both transesterification steps of telomere resolution, and is a requirement for DNA binding, distinguishing ResT from other telomere resolvases from phage and bacteria. These results advance our understanding of the molecular function of this essential enzyme involved in genome maintenance in Borrelia pathogens.},
}
RevDate: 2024-07-08
Telomere-to-telomere Citrullus super-pangenome provides direction for watermelon breeding.
Nature genetics [Epub ahead of print].
To decipher the genetic diversity within the cucurbit genus Citrullus, we generated telomere-to-telomere (T2T) assemblies of 27 distinct genotypes, encompassing all seven Citrullus species. This T2T super-pangenome has expanded the previously published reference genome, T2T-G42, by adding 399.2 Mb and 11,225 genes. Comparative analysis has unveiled gene variants and structural variations (SVs), shedding light on watermelon evolution and domestication processes that enhanced attributes such as bitterness and sugar content while compromising disease resistance. Multidisease-resistant loci from Citrullus amarus and Citrullus mucosospermus were successfully introduced into cultivated Citrullus lanatus. The SVs identified in C. lanatus have not only been inherited from cordophanus but also from C. mucosospermus, suggesting additional ancestors beyond cordophanus in the lineage of cultivated watermelon. Our investigation substantially improves the comprehension of watermelon genome diversity, furnishing comprehensive reference genomes for all Citrullus species. This advancement aids in the exploration and genetic enhancement of watermelon using its wild relatives.
Additional Links: PMID-38977857
PubMed:
Citation:
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@article {pmid38977857,
year = {2024},
author = {Zhang, Y and Zhao, M and Tan, J and Huang, M and Chu, X and Li, Y and Han, X and Fang, T and Tian, Y and Jarret, R and Lu, D and Chen, Y and Xue, L and Li, X and Qin, G and Li, B and Sun, Y and Deng, XW and Deng, Y and Zhang, X and He, H},
title = {Telomere-to-telomere Citrullus super-pangenome provides direction for watermelon breeding.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38977857},
issn = {1546-1718},
abstract = {To decipher the genetic diversity within the cucurbit genus Citrullus, we generated telomere-to-telomere (T2T) assemblies of 27 distinct genotypes, encompassing all seven Citrullus species. This T2T super-pangenome has expanded the previously published reference genome, T2T-G42, by adding 399.2 Mb and 11,225 genes. Comparative analysis has unveiled gene variants and structural variations (SVs), shedding light on watermelon evolution and domestication processes that enhanced attributes such as bitterness and sugar content while compromising disease resistance. Multidisease-resistant loci from Citrullus amarus and Citrullus mucosospermus were successfully introduced into cultivated Citrullus lanatus. The SVs identified in C. lanatus have not only been inherited from cordophanus but also from C. mucosospermus, suggesting additional ancestors beyond cordophanus in the lineage of cultivated watermelon. Our investigation substantially improves the comprehension of watermelon genome diversity, furnishing comprehensive reference genomes for all Citrullus species. This advancement aids in the exploration and genetic enhancement of watermelon using its wild relatives.},
}
RevDate: 2024-07-08
Robust evidence supports a causal link between higher birthweight and longer telomere length: a mendelian randomization study.
Frontiers in genetics, 15:1264028.
BACKGROUND: Observational studies have suggested a potential relationship between birthweight and telomere length. However, the causal link between these two parameters remains undefined. In this study, we use Mendelian Randomization (MR). This method employs genetic variants as instrumental variables, to explore the existence of causal associations and elucidate the causal relationship between birth weight and telomere length.
METHODS: We used 35 single nucleotide polymorphisms (SNPs) as instrumental variables for birth weight. These SNPs were identified from a meta-analysis involving 153,781 individuals. Furthermore, we obtained summary statistics for telomere length from a study conducted on 472,174 United Kingdom Biobank participants. To evaluate the causal estimates, we applied the random effect inverse variance weighted method (IVW) and several other MR methods, such as MR-Egger, weighted median, and MR-PRESSO, to verify the reliability of our findings.
RESULTS: Our analysis supports a significant causal relationship between genetically predicted birth weight and telomer3e length. The inverse variance weighted analysis results for birth weight (Beta = 0.048; 95%CI = 0.023 to 0.073; p < 0.001) corroborate this association.
CONCLUSION: Our study provides robust evidence supporting a causal link between higher birth weight and longer telomere length.
Additional Links: PMID-38974386
PubMed:
Citation:
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@article {pmid38974386,
year = {2024},
author = {Zhang, Z and Zhang, J and Zhang, K and Ge, X and Zhai, X},
title = {Robust evidence supports a causal link between higher birthweight and longer telomere length: a mendelian randomization study.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1264028},
pmid = {38974386},
issn = {1664-8021},
abstract = {BACKGROUND: Observational studies have suggested a potential relationship between birthweight and telomere length. However, the causal link between these two parameters remains undefined. In this study, we use Mendelian Randomization (MR). This method employs genetic variants as instrumental variables, to explore the existence of causal associations and elucidate the causal relationship between birth weight and telomere length.
METHODS: We used 35 single nucleotide polymorphisms (SNPs) as instrumental variables for birth weight. These SNPs were identified from a meta-analysis involving 153,781 individuals. Furthermore, we obtained summary statistics for telomere length from a study conducted on 472,174 United Kingdom Biobank participants. To evaluate the causal estimates, we applied the random effect inverse variance weighted method (IVW) and several other MR methods, such as MR-Egger, weighted median, and MR-PRESSO, to verify the reliability of our findings.
RESULTS: Our analysis supports a significant causal relationship between genetically predicted birth weight and telomer3e length. The inverse variance weighted analysis results for birth weight (Beta = 0.048; 95%CI = 0.023 to 0.073; p < 0.001) corroborate this association.
CONCLUSION: Our study provides robust evidence supporting a causal link between higher birth weight and longer telomere length.},
}
RevDate: 2024-07-08
Exposure to metal mixtures and telomere length in Bangladeshi children.
American journal of epidemiology pii:7708325 [Epub ahead of print].
Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (μg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.
Additional Links: PMID-38973734
Publisher:
PubMed:
Citation:
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@article {pmid38973734,
year = {2024},
author = {Farzan, SF and Niu, Z and Guo, F and Shahriar, M and Kibriya, MG and Jasmine, F and Sarwar, G and Jackson, BP and Ahsan, H and Argos, M},
title = {Exposure to metal mixtures and telomere length in Bangladeshi children.},
journal = {American journal of epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/aje/kwae181},
pmid = {38973734},
issn = {1476-6256},
abstract = {Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (μg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.},
}
RevDate: 2024-07-07
CmpDate: 2024-07-07
Telomere-to-telomere genome assembly of the goose Anser cygnoides.
Scientific data, 11(1):741.
Our study presents the assembly of a high-quality Taihu goose genome at the Telomere-to-Telomere (T2T) level. By employing advanced sequencing technologies, including Pacific Biosciences HiFi reads, Oxford Nanopore long reads, Illumina short reads, and chromatin conformation capture (Hi-C), we achieved an exceptional assembly. The T2T assembly encompasses a total length of 1,197,991,206 bp, with contigs N50 reaching 33,928,929 bp and scaffold N50 attaining 81,007,908 bp. It consists of 73 scaffolds, including 38 autosomes and one pair of Z/W sex chromosomes. Importantly, 33 autosomes were assembled without any gap, resulting in a contiguous representation. Furthermore, gene annotation efforts identified 34,898 genes, including 436,162 RNA transcripts, encompassing 806,158 exons, 743,910 introns, 651,148 coding sequences (CDS), and 135,622 untranslated regions (UTR). The T2T-level chromosome-scale goose genome assembly provides a vital foundation for future genetic improvement and understanding the genetic mechanisms underlying important traits in geese.
Additional Links: PMID-38972874
PubMed:
Citation:
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@article {pmid38972874,
year = {2024},
author = {Zhao, H and Zhou, H and Sun, G and Dong, B and Zhu, W and Mu, X and Li, X and Wang, J and Zhao, M and Yang, W and Zhang, G and Ji, R and Geng, T and Gong, D and Meng, H and Wang, J},
title = {Telomere-to-telomere genome assembly of the goose Anser cygnoides.},
journal = {Scientific data},
volume = {11},
number = {1},
pages = {741},
pmid = {38972874},
issn = {2052-4463},
mesh = {Animals ; *Geese/genetics ; *Telomere/genetics ; *Genome ; Molecular Sequence Annotation ; },
abstract = {Our study presents the assembly of a high-quality Taihu goose genome at the Telomere-to-Telomere (T2T) level. By employing advanced sequencing technologies, including Pacific Biosciences HiFi reads, Oxford Nanopore long reads, Illumina short reads, and chromatin conformation capture (Hi-C), we achieved an exceptional assembly. The T2T assembly encompasses a total length of 1,197,991,206 bp, with contigs N50 reaching 33,928,929 bp and scaffold N50 attaining 81,007,908 bp. It consists of 73 scaffolds, including 38 autosomes and one pair of Z/W sex chromosomes. Importantly, 33 autosomes were assembled without any gap, resulting in a contiguous representation. Furthermore, gene annotation efforts identified 34,898 genes, including 436,162 RNA transcripts, encompassing 806,158 exons, 743,910 introns, 651,148 coding sequences (CDS), and 135,622 untranslated regions (UTR). The T2T-level chromosome-scale goose genome assembly provides a vital foundation for future genetic improvement and understanding the genetic mechanisms underlying important traits in geese.},
}
MeSH Terms:
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Animals
*Geese/genetics
*Telomere/genetics
*Genome
Molecular Sequence Annotation
RevDate: 2024-07-05
The association between dietary selenium intake and telomere length in hypertension.
Journal of clinical hypertension (Greenwich, Conn.) [Epub ahead of print].
Telomere length is closely linked to biological aging, oxidative stress, and the development of cardiovascular diseases. This study aimed to assess the association between dietary selenium intake and telomere length in individuals with hypertension. Data on dietary selenium intake were captured through the National Health and Nutrition Examination Survey (NHANES) computer-assisted dietary interview system (CADI). Telomere length determination entailed selecting blood samples from all participants in the NHANES database. The analysis was performed using Analysis System software, with Empower stats utilized for data analysis. Results showed that there was a significant association between dietary selenium intake and telomere length in hypertension, particularly within the female group. In female hypertension cases, a 1 mcg increase in dietary selenium intake corresponded to a telomere length increase of 1.19 bp, even after adjusting for age, race, BMI, marital status, physical activity, energy intake, and stroke history. The relationship between dietary selenium intake and telomere length exhibited a linear pattern in female hypertension patients. This study identified a positive association between dietary selenium intake and telomere length in hypertension, particularly within the female group.
Additional Links: PMID-38967394
Publisher:
PubMed:
Citation:
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@article {pmid38967394,
year = {2024},
author = {Liang, C and Zhao, R and Du, J and Zhao, G and Zhang, Y},
title = {The association between dietary selenium intake and telomere length in hypertension.},
journal = {Journal of clinical hypertension (Greenwich, Conn.)},
volume = {},
number = {},
pages = {},
doi = {10.1111/jch.14861},
pmid = {38967394},
issn = {1751-7176},
support = {82100283//National Natural Science Foundation of China/ ; 82270407//National Natural Science Foundation of China/ ; 232102310181//The Scientific and Technological Project of Henan Province/ ; },
abstract = {Telomere length is closely linked to biological aging, oxidative stress, and the development of cardiovascular diseases. This study aimed to assess the association between dietary selenium intake and telomere length in individuals with hypertension. Data on dietary selenium intake were captured through the National Health and Nutrition Examination Survey (NHANES) computer-assisted dietary interview system (CADI). Telomere length determination entailed selecting blood samples from all participants in the NHANES database. The analysis was performed using Analysis System software, with Empower stats utilized for data analysis. Results showed that there was a significant association between dietary selenium intake and telomere length in hypertension, particularly within the female group. In female hypertension cases, a 1 mcg increase in dietary selenium intake corresponded to a telomere length increase of 1.19 bp, even after adjusting for age, race, BMI, marital status, physical activity, energy intake, and stroke history. The relationship between dietary selenium intake and telomere length exhibited a linear pattern in female hypertension patients. This study identified a positive association between dietary selenium intake and telomere length in hypertension, particularly within the female group.},
}
RevDate: 2024-07-05
A telomere-to-telomere gap-free reference genome assembly of avocado provides useful resources for identifying genes related to fatty acid biosynthesis and disease resistance.
Horticulture research, 11(7):uhae119 pii:uhae119.
Avocado (Persea americana Mill.) is an economically valuable plant because of the high fatty acid content and unique flavor of its fruits. Its fatty acid content, especially the relatively high unsaturated fatty acid content, provides significant health benefits. We herein present a telomere-to-telomere gapless genome assembly (841.6 Mb) of West Indian avocado. The genome contains 40 629 predicted protein-coding genes. Repeat sequences account for 57.9% of the genome. Notably, all telomeres, centromeres, and a nucleolar organizing region are included in this genome. Fragments from these three regions were observed via fluorescence in situ hybridization. We identified 376 potential disease resistance-related nucleotide-binding leucine-rich repeat genes. These genes, which are typically clustered on chromosomes, may be derived from gene duplication events. Five NLR genes (Pa11g0262, Pa02g4855, Pa07g3139, Pa07g0383, and Pa02g3196) were highly expressed in leaves, stems, and fruits, indicating they may be involved in avocado disease responses in multiple tissues. We also identified 128 genes associated with fatty acid biosynthesis and analyzed their expression patterns in leaves, stems, and fruits. Pa02g0113, which encodes one of 11 stearoyl-acyl carrier protein desaturases mediating C18 unsaturated fatty acid synthesis, was more highly expressed in the leaves than in the stems and fruits. These findings provide valuable insights that enhance our understanding of fatty acid biosynthesis in avocado.
Additional Links: PMID-38966866
Full Text:
Publisher:
PubMed:
Citation:
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@article {pmid38966866,
year = {2024},
author = {Yang, T and Cai, Y and Huang, T and Yang, D and Yang, X and Yin, X and Zhang, C and Yang, Y and Yang, Y},
title = {A telomere-to-telomere gap-free reference genome assembly of avocado provides useful resources for identifying genes related to fatty acid biosynthesis and disease resistance.},
journal = {Horticulture research},
volume = {11},
number = {7},
pages = {uhae119},
doi = {10.1093/hr/uhae119},
pmid = {38966866},
issn = {2662-6810},
abstract = {Avocado (Persea americana Mill.) is an economically valuable plant because of the high fatty acid content and unique flavor of its fruits. Its fatty acid content, especially the relatively high unsaturated fatty acid content, provides significant health benefits. We herein present a telomere-to-telomere gapless genome assembly (841.6 Mb) of West Indian avocado. The genome contains 40 629 predicted protein-coding genes. Repeat sequences account for 57.9% of the genome. Notably, all telomeres, centromeres, and a nucleolar organizing region are included in this genome. Fragments from these three regions were observed via fluorescence in situ hybridization. We identified 376 potential disease resistance-related nucleotide-binding leucine-rich repeat genes. These genes, which are typically clustered on chromosomes, may be derived from gene duplication events. Five NLR genes (Pa11g0262, Pa02g4855, Pa07g3139, Pa07g0383, and Pa02g3196) were highly expressed in leaves, stems, and fruits, indicating they may be involved in avocado disease responses in multiple tissues. We also identified 128 genes associated with fatty acid biosynthesis and analyzed their expression patterns in leaves, stems, and fruits. Pa02g0113, which encodes one of 11 stearoyl-acyl carrier protein desaturases mediating C18 unsaturated fatty acid synthesis, was more highly expressed in the leaves than in the stems and fruits. These findings provide valuable insights that enhance our understanding of fatty acid biosynthesis in avocado.},
}
RevDate: 2024-07-04
Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.
Ecotoxicology and environmental safety, 281:116650 pii:S0147-6513(24)00726-7 [Epub ahead of print].
Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 μm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.
Additional Links: PMID-38964064
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PubMed:
Citation:
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@article {pmid38964064,
year = {2024},
author = {Chang-Chien, J and Kuo, ML and Tseng, YL and Huang, HY and Tsai, HJ and Yao, TC},
title = {Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.},
journal = {Ecotoxicology and environmental safety},
volume = {281},
number = {},
pages = {116650},
doi = {10.1016/j.ecoenv.2024.116650},
pmid = {38964064},
issn = {1090-2414},
abstract = {Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 μm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.},
}
RevDate: 2024-07-04
CmpDate: 2024-07-04
Telomere C-Strand Fill-In Machinery: New Insights into the Human CST-DNA Polymerase Alpha-Primase Structures and Functions.
Sub-cellular biochemistry, 104:73-100.
Telomeres at the end of eukaryotic chromosomes are extended by a specialized set of enzymes and telomere-associated proteins, collectively termed here the telomere "replisome." The telomere replisome acts on a unique replicon at each chromosomal end of the telomeres, the 3' DNA overhang. This telomere replication process is distinct from the replisome mechanism deployed to duplicate the human genome. The G-rich overhang is first extended before the complementary C-strand is filled in. This overhang is extended by telomerase, a specialized ribonucleoprotein and reverse transcriptase. The overhang extension process is terminated when telomerase is displaced by CTC1-STN1-TEN1 (CST), a single-stranded DNA-binding protein complex. CST then recruits DNA polymerase α-primase to complete the telomere replication process by filling in the complementary C-strand. In this chapter, the recent structure-function insights into the human telomere C-strand fill-in machinery (DNA polymerase α-primase and CST) will be discussed.
Additional Links: PMID-38963484
PubMed:
Citation:
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@article {pmid38963484,
year = {2024},
author = {Lim, CJ},
title = {Telomere C-Strand Fill-In Machinery: New Insights into the Human CST-DNA Polymerase Alpha-Primase Structures and Functions.},
journal = {Sub-cellular biochemistry},
volume = {104},
number = {},
pages = {73-100},
pmid = {38963484},
issn = {0306-0225},
mesh = {Humans ; *Telomere/metabolism/genetics ; *DNA Polymerase I/metabolism/genetics/chemistry ; *DNA Primase/metabolism/genetics/chemistry ; *Telomere-Binding Proteins/metabolism/genetics ; *DNA Replication ; Telomerase/metabolism/genetics ; },
abstract = {Telomeres at the end of eukaryotic chromosomes are extended by a specialized set of enzymes and telomere-associated proteins, collectively termed here the telomere "replisome." The telomere replisome acts on a unique replicon at each chromosomal end of the telomeres, the 3' DNA overhang. This telomere replication process is distinct from the replisome mechanism deployed to duplicate the human genome. The G-rich overhang is first extended before the complementary C-strand is filled in. This overhang is extended by telomerase, a specialized ribonucleoprotein and reverse transcriptase. The overhang extension process is terminated when telomerase is displaced by CTC1-STN1-TEN1 (CST), a single-stranded DNA-binding protein complex. CST then recruits DNA polymerase α-primase to complete the telomere replication process by filling in the complementary C-strand. In this chapter, the recent structure-function insights into the human telomere C-strand fill-in machinery (DNA polymerase α-primase and CST) will be discussed.},
}
MeSH Terms:
show MeSH Terms
hide MeSH Terms
Humans
*Telomere/metabolism/genetics
*DNA Polymerase I/metabolism/genetics/chemistry
*DNA Primase/metabolism/genetics/chemistry
*Telomere-Binding Proteins/metabolism/genetics
*DNA Replication
Telomerase/metabolism/genetics
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