Viewport Size Code:
Login | Create New Account


About | Classical Genetics | Timelines | What's New | What's Hot

About | Classical Genetics | Timelines | What's New | What's Hot


Bibliography Options Menu

Hide Abstracts   |   Hide Additional Links
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: Telomeres

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 21 Sep 2023 at 01:55 Created: 


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: 2023-09-18

Wong JY, Shu XO, Hu W, et al (2023)

Associations between longer leukocyte telomere length and increased lung cancer risk among never smokers in urban China.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:729118 [Epub ahead of print].

BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically-predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology.

METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's and Men's Health Studies (SWHS: 798 cases and 792 controls; SMHS: 161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. Additionally, we conducted Mendelian Randomization (MR) using MR-PRESSO.

RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (p-trendLTL=4x10-6; p-trendgTL=3x10-4). Similarly among never-smoking men, longer measured LTL was associated with over triple the risk compared to those with the shortest (OR=3.48, 95%CI: 1.85, 6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL=1.19 (95%CI: 1.03, 1.37; p=0.03).

CONCLUSIONS: Longer pre-diagnostic leukocyte telomere length is associated with increased lung cancer risk among never smokers.

IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.

RevDate: 2023-09-19
CmpDate: 2023-09-19

Bhat GR, Jamwal RS, Sethi I, et al (2023)

Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India.

BMC cancer, 23(1):874.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk.

METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR.

RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004).

CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

RevDate: 2023-09-19
CmpDate: 2023-09-18

Liu X, Arshad R, Wang X, et al (2023)

The phased telomere-to-telomere reference genome of Musa acuminata, a main contributor to banana cultivars.

Scientific data, 10(1):631.

Musa acuminata is a main wild contributor to banana cultivars. Here, we reported a haplotype-resolved and telomere-to-telomere reference genome of M. acuminata by incorporating PacBio HiFi reads, Nanopore ultra-long reads, and Hi-C data. The genome size of the two haploid assemblies was estimated to be 469.83 Mb and 470.21 Mb, respectively. Multiple assessments confirmed the contiguity (contig N50: 16.53 Mb and 18.58 Mb; LAI: 20.18 and 19.48), completeness (BUSCOs: 98.57% and 98.57%), and correctness (QV: 45.97 and 46.12) of the genome. The repetitive sequences accounted for about half of the genome size. In total, 40,889 and 38,269 protein-coding genes were annotated in the two haploid assemblies, respectively, of which 9.56% and 3.37% were newly predicted. Genome comparison identified a large reciprocal translocation involving 3 Mb and 10 Mb from chromosomes 01 and 04 within M. acuminata. This reference genome of M. acuminata provides a valuable resource for further understanding of subgenome evolution of Musa species, and precise genetic improvement of banana.

RevDate: 2023-09-18

Tichy ED, Lee JH, Li G, et al (2023)

Impacts of radiation exposure, hindlimb unloading, and recovery on murine skeletal muscle cell telomere length.

NPJ microgravity, 9(1):76.

Astronauts are exposed to harsh conditions, including cosmic radiation and microgravity. Spaceflight elongates human telomeres in peripheral blood, which shorten upon return to Earth and approach baseline levels during postflight recovery. Astronauts also encounter muscle atrophy, losing up to 20% loss of muscle mass on spaceflights. Telomere length changes in muscle cells of astronauts remain unexplored. This study investigates telomere alterations in grounded mice experiencing radiation exposure and muscle atrophy, via a hindlimb unloading spaceflight mimicking model. We find telomere lengthening is present in muscle stem cells and in myofiber nuclei, but not in muscle-resident endothelial cells. We further assessed telomere length in the model following hindlimb unloading recovery. We find that telomere length failed to return to baseline values. Our results suggest a role for telomeres in muscle acclimatization, which is relevant for the well-being of astronauts in space, and upon their return to Earth.

RevDate: 2023-09-15

Manzato C, Larini L, Pegorar CO, et al (2023)

TERRA expression is regulated by the telomere-binding proteins POT-1 and POT-2 in Caenorhabditis elegans.

Nucleic acids research pii:7275007 [Epub ahead of print].

Several aspects of telomere biology are regulated by the telomeric repeat-containing RNA TERRA. While TERRA expression is conserved through evolution, species-specific mechanisms regulate its biogenesis and function. Here we report on the expression of TERRA in Caenorhabditis elegans. We show that C. elegans TERRA is regulated by the telomere-binding proteins POT-1 and POT-2 which repress TERRA in a telomere-specific manner. C. elegans TERRA transcripts are heterogeneous in length and form discrete nuclear foci, as detected by RNA FISH, in both postmitotic and germline cells; a fraction of TERRA foci localizes to telomeres. Interestingly, in germ cells, TERRA is expressed in all stages of meiotic prophase I, and it increases during pachytene, a stage in meiosis when homologous recombination is ongoing. We used the MS2-GFP system to study the spatiotemporal dynamics of single-telomere TERRA molecules. Single particle tracking revealed different types of motilities, suggesting complex dynamics of TERRA transcripts. Finally, we unveiled distinctive features of C. elegans TERRA, which is regulated by telomere shortening in a telomere-specific manner, and it is upregulated in the telomerase-deficient trt-1; pot-2 double mutant prior to activation of the alternative lengthening mechanism ALT. Interestingly, in these worms TERRA displays distinct dynamics with a higher fraction of fast-moving particles.

RevDate: 2023-09-14

Jalan-Sakrikar N, Anwar A, Yaqoob U, et al (2023)

Telomere dysfunction promotes cholangiocyte senescence and biliary fibrosis in Primary Sclerosing Cholangitis.

JCI insight pii:170320 [Epub ahead of print].

Cellular senescence and biliary fibrosis are prototypical features of obliterative cholangiopathies, such as Primary Sclerosing Cholangitis (PSC). Telomere dysfunction can lead to senescence either through telomere erosion or damaged telomeres. Our goal was to investigate a mechanistic relationship between telomere damage and biliary fibrosis in PSC. Telomere attrition was observed in the bile ducts of PSC patients along with a reduction in telomerase reverse transcriptase (TERT) expression compared to normal livers. Similarly, liver tissue from mice models of biliary fibrosis showed telomere attrition with increased damage at telomeres measured as telomere-associated foci (TAF). Cellular models of senescence induction increased the TAFs in cholangiocytes. This coincided with decreased TERT expression and increased senescence, which was rescued by modulating TERT levels. Epigenetic analysis revealed increased acquisition of repressive histone methylation at the TERT promoter which correlated with decreased TERT transcription. Cholangiocyte-selective deletion of TERT in mice exacerbated fibrosis whereas androgen therapy towards telomerase rescued liver fibrosis and liver function in genetic mouse model of PSC. Our results demonstrate a mechanistic role for telomere dysfunction in cellular senescence and fibrosis that characterize PSC. This suggests that PSC may be, in part, a telomere biology disorder, and identifies TERT as a potential therapeutic target.

RevDate: 2023-09-16

Cao Z, Hou Y, C Xu (2023)

Leucocyte telomere length, brain volume and risk of dementia: a prospective cohort study.

General psychiatry, 36(4):e101120.

BACKGROUND: The evidence regarding the association between leucocyte telomere length (LTL) and brain health is sparse and inconclusive.

AIMS: To investigate the associations of LTL with brain structure and the risk of dementia based on a large-scale prospective study.

METHODS: LTL in the peripheral blood was measured by the quantitative polymerase chain reaction (qPCR) assay from 439 961 individuals in the UK Biobank recruited between 2006 and 2010 and followed up until 2020. Electronic health records were used to record the incidence of dementia, including Alzheimer's disease (AD) and vascular dementia (VD). The brain structure, including total and regional brain volume, of 38 740 participants was then assessed by magnetic resonance imaging (MRI).

RESULTS: During a median follow-up of 11.6 years, a total of 5 820 (1.3%) dementia cases were documented. The restricted cubic spline model showed significant overall associations between LTL and the risk of dementia and AD (p for overall <0.05). The multivariable adjusted hazard ratios (HRs) for the lowest LTL tertile compared with the highest LTL tertile were 1.14 (95% confidence interval (CI): 1.06 to 1.21) for dementia, 1.28 (95% CI: 1.12 to 1.46) for AD and 1.18 (95% CI: 0.98 to 1.42) for VD. Furthermore, we found that shorter LTL was associated with smaller total brain volume (β=-0.012 8, p=0.003), white matter volume (β=-0.022 4, p<0.001), hippocampus volume (β=-0.017 2, p<0.001), thalamus volume (β=-0.023 9, p<0.001) and accumbens (β=-0.015 5, p=0.001).

CONCLUSIONS: Shorter LTL is associated with total and regional brain structure and a higher risk of incident dementia and AD, implying the potential of telomere length as a predictive biomarker of brain health.

RevDate: 2023-09-14

Houminer-Klepar N, Bord S, Epel E, et al (2023)

Working status of first-time postpartum mothers and telomere length - a one-year prospective study.

Journal of occupational and environmental medicine pii:00043764-990000000-00404 [Epub ahead of print].

OBJECTIVE: Transitioning to motherhood can create work family conflicts affecting mothers' health. Although employment is generally associated with longer telomeres, this may diminish during the early years of child-rearing. This study aimed to assess the impact of work re-entry on TL among first-time mothers.

METHODS: In this one-year prospective study, a total of 103 first time postpartum mothers participated from two medical institutions in Northern Israel, they completed validated questionnaires, reported their current working status and provided dried blood spots measuring telomere length (TL).

RESULTS: We found that working status significantly predicted change in TL and was negatively correlated with change in TL over time (β = - 0.245, 95% CI -0.169, -0.018, p = 0.016).

CONCLUSIONS: Identifying ideal timing of work re-entry is recommended for first-time postpartum mother's optimal health and TL.

RevDate: 2023-09-14
CmpDate: 2023-09-14

Rahman ST, Waterhouse M, Pham H, et al (2023)

Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

The journal of nutrition, health & aging, 27(8):609-616.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio).

Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation.

RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration.

CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.

RevDate: 2023-09-14

Huang HR, Liu X, Arshad R, et al (2023)

Telomere-to-telomere haplotype-resolved reference genome reveals subgenome divergence and disease resistance in triploid Cavendish banana.

Horticulture research, 10(9):uhad153.

Banana is one of the most important crops of the world. Cavendish-type bananas, which have a monospecific Musa acuminata origin (AAA), account for around half of the global banana production, thereby are of great significance for human societies. However, until now, the high-quality haplotype-resolved reference genome was still undecoded for banana cultivars. Here, we reported the telomere-to-telomere (T2T) and haplotype-resolved reference genome of 'Baxijiao' (Cavendish) consisting of three haploid assemblies. The sizes of the three haploid assemblies were estimated to be 477.16 Mb, 477.18 Mb, and 469.57 Mb, respectively. Although with monospecific origins, the three haploid assemblies showed great differences with low levels of sequence collinearity. Several large reciprocal translocations were identified among chromosomes 1, 4, and 7. An expansion of gene families that might affect fruit quality and aroma was detected, such as those belonging to sucrose/disaccharide/oligosaccharide catabolic processes, sucrose metabolic process, starch metabolic process, and aromatic compound biosynthetic process. Besides, an expansion of gene families related to anther and pollen development was observed, which could be associated with parthenocarpy and sterility of the Cavendish cultivar. Finally, much fewer resistance genes were identified in 'Baxijiao' than in M. acuminata, particularly in the gene clusters in chromosomes 3 and 10, providing potential targets to explore for molecular analysis of disease resistance in banana. This T2T haplotype-resolved reference genome will thus be a valuable genetic resource for biological studies, molecular breeding, and genetic improvement of banana.

RevDate: 2023-09-11

Han D, Zhu Y, Choudhry AA, et al (2023)

Association of telomere length with risk of lung cancer: A large prospective cohort study from the UK Biobank.

Lung cancer (Amsterdam, Netherlands), 184:107358 pii:S0169-5002(23)00896-6 [Epub ahead of print].

OBJECTIVES: Leukocyte telomere length (LTL) is associated with a wide variety of diseases, including cancer. However, findings regarding the association between LTL and the risk for lung cancer have been inconclusive and inconsistent across previous observational studies.

METHODS: This prospective cohort study included data from 425,146 participants 37-73 years of age housed in the UK Biobank. Quantitative polymerase chain reaction (qPCR) was used to measure LTL in baseline DNA samples. A multivariate Cox proportional hazards model was used to evaluate the relationship between LTL and the risk for lung cancer.

RESULTS: An increase in LTL per interquartile range (IQR) was associated with a 9% increase in the risk for lung cancer (hazard ratio [HR] 1.09 [95% confidence interval (CI) 1.03-1.16]). Participants in the highest LTL quintile exhibited an approximately 25% elevated risk for developing lung cancer (HR 1.25 [95% CI 1.09-1.45]) compared with those in the lowest quintile. The relationship between per IQR increase in LTL and elevated risk for lung cancer was greater in the histological subtype of adenocarcinoma (HR 1.30 [95% CI 1.18-1.43]), female sex (HR 1.16 [95% CI 1.06-1.26]), non-smokers (HR 1.45 [95% CI 1.23-1.71]), and individuals with high genetic risk for lung cancer (HR 1.18 [95% CI 1.03-1.34]), respectively. Surprisingly, a per IQR increase in LTL was associated with increased risks for both lung adenocarcinoma (HR 1.56 [95% CI 1.24-1.96]) and squamous cell carcinoma (HR 2.01 [95% CI 1.13-3.56]) in never smokers.

CONCLUSIONS: Longer LTL was associated with an elevated risk for lung cancer, particularly for adenocarcinoma and squamous cell carcinoma in never smokers. The results suggest the potential of telomeres as non-invasive biomarkers for the early screening of lung cancer, particularly in non-smokers, who are typically overlooked.

RevDate: 2023-09-13

Yu W, Mei Y, Lu Z, et al (2023)

The causal relationship between genetically determined telomere length and meningiomas risk.

Frontiers in neurology, 14:1178404.

BACKGROUND: Studies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors.

METHODS: We used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR).

RESULTS: In the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10[-5]], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected.

CONCLUSION: In brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations.

RevDate: 2023-09-12

Anonymous (2023)

"Interstitial lung abnormalities are associated with decreased mean telomere length." R.K. Putman, G.T. Axelsson, S.Y. Ash, et al. Eur Respir J 2022; 60: 2101814.

The European respiratory journal, 62(3): pii:62/3/2151814.

RevDate: 2023-09-11

Martinez S, JD Jones (2023)

A pilot study examining the relationship between chronic heroin use and telomere length among individuals of African ancestry.

Pharmacology, biochemistry, and behavior, 231:173631 pii:S0091-3057(23)00118-1 [Epub ahead of print].

BACKGROUND: Prior research has suggested a possible link between heroin use and shortened telomere length (TL), a marker of cellular aging and genomic stability. We sought to replicate these findings by examining the relationship between TL and heroin use among individuals of African ancestry.

METHODS: This cross-sectional study examined TL among 57 participants [17.5 % female; mean age 48.0 (±6.80) years] of African ancestry with Opioid Use Disorder (OUD) and a mean heroin use duration of 18.2 (±10.7) years. Quantitative polymerase chain reaction (qPCR) was used to calculate TL as the ratio between telomere repeat copy number (T) and a single-copy gene, copy number (S). The primary dependent variable was TL (T/S Ratio) measured in kilobase pairs. Covariates included heroin use years and personality traits. Using a hybrid approach, multiple linear regression and Bayesian linear regression examined the association of chronological age, heroin use years and personality traits with TL.

RESULTS: The multiple linear regression model fit the data well, R[2] = 0.265, F(7,49) = 2.53, p < .026. Chronological age (β = -0.36, p = .017), neuroticism (β = 0.46, p = .044), and conscientiousness (β = 0.52, p = .040) were significant predictors of TL. Bayesian linear regression provided moderate support for the alternate hypothesis that chronological age and TL are associated, BF[10] = 5.77, R[2] = 0.120. The posterior summary of the coefficient was M = 0.719 (SD = 0.278, 95 % credible interval [-1.28, -0.163]).

CONCLUSIONS: Contrary to prior studies, these findings suggest that heroin use duration may not be significantly associated with TL among individuals of African ancestry, highlighting the need for more rigorous research to elucidate the complexity of this relationship.

RevDate: 2023-09-09

Sullivan DI, Bello FM, Silva AG, et al (2023)

Intact mitochondrial function in the setting of telomere-induced senescence.

Aging cell [Epub ahead of print].

Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.

RevDate: 2023-09-09

Kreilmeier-Berger T, Aupperle-Lellbach H, Reifinger M, et al (2023)

Alternative Lengthening of Telomeres Is Rare in Canine Histiocytic Sarcoma.

Cancers, 15(17): pii:cancers15174214.

Cancer cells activate telomere maintenance mechanisms (TMMs) to overcome senescence and thus are targets for TMM-specific therapies. Telomerase-independent alternative lengthening of telomeres (ALT) is frequently utilized as a TMM in human sarcoma subtypes. Histiocytic sarcoma (HS) is a rare but aggressive tumor of hematopoietic origin with unknown ALT incidence in humans. ALT has been identified in canine HS, a tumor type comparable to human HS that occurs with high rates in certain canine breeds such as Bernese mountain dogs (BMDs). This retrospective study characterized the frequency of ALT in BMD and non-BMD patients diagnosed with HS as surrogates for humans. Formalin-fixed paraffin-embedded tumor samples from 63 dogs at two centers, including 47 BMDs, were evaluated for their ALT activity and relative telomere content (TC) using a radiolabel C-circle assay (CCA). Known ALT-positive samples served as controls. CCA-positive cases were validated via FISH. Two BMD samples showed ALT activity of 1-14% compared to controls. All other samples were ALT-negative. The TC did not correlate with the CCA results. ALT positivity was validated by the appearance of ultrabright telomere foci. Low ALT activity was present in 4% of BMDs with HS and therefore does not appear to be a common target for therapeutic approaches but can have diagnostic value.

RevDate: 2023-09-08

Benitez-Roig V, Martínez-Carpio PA, Trelles MA, et al (2023)

Clinical and laboratory results in vaginal wall restoration using a fractional-pixel-CO2 laser: histological findings and changes in the Ki67 protein and telomere length.

Lasers in medical science, 38(1):206.

Thermal deposition of laser energy in the vaginal epithelium in genitourinary syndrome of menopause (GSM) results in clinical and biological effects, but many cellular and molecular changes indicating cell proliferation or senescence inhibition are unknown. The aim of this study is to evaluate the clinical efficacy of the fractional-pixel-CO2 laser in the possible improvement of GMS signs and symptoms that can be correlated with histological changes or with cellular or molecular indicators of restoration. A detailed prospective study was designed to assess 17 women diagnosed with GSM who were treated intravaginally with two laser sessions. Seven non-treated women diagnosed with GSM were used as controls. Three validated outcome questionnaires for assessment of quality of sexual life and urinary incontinence were performed. Vaginal biopsies were collected before the first laser treatment and 4 months following the second session. Histological status, elastin, collagen, and hyaluronic acid content of the biopsies were also evaluated. Cell proliferation was assessed by Ki67 staining. Telomere length (TL) was measured by qPCR. The results show an improvement of the clinical symptoms of GSM (p < 0.05), vaginal epithelium recovery and enhancement of collagen (p < 0.05), elastic fibers (p < 0.005), and hyaluronic acid (p < 0.0005) content in the lamina propria after fractional-pixel-CO2 laser treatment. The laser treatment induced a significant rise on the TL of vaginal epithelial cells (VECs), and a positive correlation was found between the improvements of the collagen and hyaluronic acid content and TL changes (r = 0.82, p < 0.05; r = 0.38, p < 0.05). The percentage of proliferative Ki67-positive VECs was increased in patients whose vaginal TL lengthened after laser treatment (p < 0.05). In conclusion, the results indicate that laser treatment may induce restoration of the vaginal epithelium which is associated to increased TL and proliferation in the VECs. Performing a TL assay could be a suitable tool to evaluate the efficacy of vaginal laser treatment.

RevDate: 2023-09-09

Yin F, Zhou Y, Xie D, et al (2023)

Effects of nanomaterial exposure on telomere dysfunction, hallmarks of mammalian and zebrafish cell senescence, and zebrafish mortality.

Ageing research reviews, 91:102062 pii:S1568-1637(23)00221-0 [Epub ahead of print].

Environmental and occupational exposure to hazardous substances accelerates biological aging. However, the toxic effects of nanomaterials on telomere and cellular senescence (major hallmarks of the biological aging) remained controversial. This study was to synthesize all published evidence to explore the effects of nanomaterial exposure on the telomere change, cellular senescence and mortality of model animals. Thirty-five studies were included by searching electronic databases (PubMed, Embase and Web of Science). The pooled analysis by Stata 15.0 software showed that compared with the control, nanomaterial exposure could significantly shorten the telomere length [measured as kbp: standardized mean difference (SMD) = -1.88; 95% confidence interval (CI) = -3.13 - - 0.64; % of control: SMD = -1.26; 95%CI = -2.11- - 0.42; < 3 kbp %: SMD = 5.76; 95%CI = 2.92 - 8.60), increase the telomerase activity (SMD = -1.00; 95%CI = -1.74 to -0.26), senescence-associated β-galactosidase levels in cells (SMD = 8.20; 95%CI = 6.05 - 10.34) and zebrafish embryos (SMD = 7.32; 95%CI = 4.70 - 9.94) as well as the mortality of zebrafish (SMD = 3.83; 95%CI = 2.94 - 4.72)]. The expression levels of telomerase TERT, shelterin components (TRF1, TRF2 and POT1) and senescence biomarkers (p21, p16) were respectively identified to be decreased or increased in subgroup analyses. In conclusion, this meta-analysis demonstrates that nanomaterial exposure is associated with telomere attrition, cell senescence and organismal death.

RevDate: 2023-09-06

Fan G, Liu Q, Bi J, et al (2023)

Association between female-specific reproductive factors and leukocyte telomere length.

Human reproduction (Oxford, England) pii:7260908 [Epub ahead of print].

STUDY QUESTION: What are the associations between female-specific reproductive factors and leukocyte telomere length (LTL)?

SUMMARY ANSWER: Early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of oral contraceptives (OCs) and hormone replacement therapy (HRT) were associated with shorter LTL.

WHAT IS KNOWN ALREADY: Reproductive factors have been associated with age-related diseases, but their associations with cellular aging, as indicated by LTL, are unclear.

STUDY DESIGN, SIZE, DURATION: This population-based study included 224 965 women aged 40-69 years from the UK Biobank between 2006 and 2010.

Women aged 40-69 were included. Female-specific reproductive factors, including age at menarche, age at natural menopause, reproductive lifespan, number of live births, age at first live birth, history of stillbirth, history of miscarriage, and use of OCs and HRT were self-reported. LTL was measured using a validated polymerase chain reaction method. Multiple linear regression and restricted cubic spline models were applied to explore the association between each reproductive factor and LTL.

After adjustment for potential confounders, early menarche (<12 years; percent change, per unit change in LTL Z score: -1.29%, 95% CI: -2.32%, -0.26%), early menopause (<45 years; percent change: -7.18%, 95% CI: -8.87%, -5.45%), short reproductive lifespan (<30 years; percent change: -6.10%, 95% CI: -8.14%, -4.01%), multiparity (percent change: -3.38%, 95% CI: -4.38%, -2.37%), early age at first live birth (<20 years; percent change: -4.46%, 95% CI: -6.00%, -2.90%), and use of OCs (percent change: -1.10%, 95% CI: -2.18%, -0.02%) and HRT (percent change: -3.72%, 95% CI: -4.63%, -2.80%) were all significantly associated with shorter LTL. However, no significant association was found for history of miscarriage and stillbirth. We observed nonlinear relationships of age at menarche, age at natural menopause, reproductive lifespan, and age at first live birth with LTL (Pnonlinear < 0.05).

Considering that the participants were predominantly of European ethnicity, the findings may not be generalizable to women of other ethnic backgrounds.

Our findings suggest that early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of OCs and HRT were associated with shorter LTL, which has been linked to various chronic diseases. The accelerated shortening of telomeres may potentially contribute to the development of chronic diseases related to reproductive factors.

This study was funded by the National Natural Science Foundation of China (82003479, 82073660), Hubei Provincial Natural Science Foundation of China (2023AFB663), and the China Postdoctoral Science Foundation (2019M662646, 2020T130220). The authors have no competing interests to disclose.


RevDate: 2023-09-04

Ferrer A, Lasho T, Fernandez JA, et al (2023)

Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants.

Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.

RevDate: 2023-09-05
CmpDate: 2023-09-05

Han X, Yan Z, Fan K, et al (2023)

The combined signatures of telomere and immune cell landscape provide a prognostic and therapeutic biomarker in glioma.

Frontiers in immunology, 14:1220100.

BACKGROUND: Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma.

METHODS: This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways.

RESULTS: The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001).

CONCLUSION: Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.

RevDate: 2023-09-03

Zhou HH, Jin B, Liao Y, et al (2023)

Associations of Various Physical Activities With Mortality and Life Expectancy Are Mediated by Telomere Length.

Journal of the American Medical Directors Association pii:S1525-8610(23)00710-7 [Epub ahead of print].

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality.

DESIGN: Prospective cohort study.

SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed.

METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy.

RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001).

CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

RevDate: 2023-09-02

Casagrande S, Loveland JL, Oefele M, et al (2023)

Dietary nucleotides can prevent glucocorticoid-induced telomere attrition in a fast-growing wild vertebrate.

Molecular ecology [Epub ahead of print].

Telomeres are chromosome protectors that shorten during eukaryotic cell replication and in stressful conditions. Developing individuals are susceptible to telomere erosion when their growth is fast and resources are limited. This is critical because the rate of telomere attrition in early life is linked to health and life span of adults. The metabolic telomere attrition hypothesis (MeTA) suggests that telomere dynamics can respond to biochemical signals conveying information about the organism's energetic state. Among these signals are glucocorticoids, hormones that promote catabolic processes, potentially impairing costly telomere maintenance, and nucleotides, which activate anabolic pathways through the cellular enzyme target of rapamycin (TOR), thus preventing telomere attrition. During the energetically demanding growth phase, the regulation of telomeres in response to two contrasting signals - one promoting telomere maintenance and the other attrition - provides an ideal experimental setting to test the MeTA. We studied nestlings of a rapidly developing free-living passerine, the great tit (Parus major), that either received glucocorticoids (Cort-chicks), nucleotides (Nuc-chicks) or a combination of both (NucCort-chicks), comparing these with controls (Cnt-chicks). As expected, Cort-chicks showed telomere attrition, while NucCort- and Nuc-chicks did not. NucCort-chicks was the only group showing increased expression of a proxy for TOR activation (the gene TELO2), of mitochondrial enzymes linked to ATP production (cytochrome oxidase and ATP-synthase) and a higher efficiency in aerobically producing ATP. NucCort-chicks had also a higher expression of telomere maintenance genes (shelterin protein TERF2 and telomerase TERT) and of enzymatic antioxidant genes (glutathione peroxidase and superoxide dismutase). The findings show that nucleotide availability is crucial for preventing telomere erosion during fast growth in stressful environments.

RevDate: 2023-08-31

Roisné-Hamelin F, S Marcand (2023)

All roads lead to MRN regulation at telomeres: different paths to one solution.

Nature structural & molecular biology [Epub ahead of print].

RevDate: 2023-08-31

Myler LR, Toia B, Vaughan CK, et al (2023)

DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres.

Nature structural & molecular biology [Epub ahead of print].

Telomeres replicated by leading-strand synthesis lack the 3' overhang required for telomere protection. Surprisingly, resection of these blunt telomeres is initiated by the telomere-specific 5' exonuclease Apollo rather than the Mre11-Rad50-Nbs1 (MRN) complex, the nuclease that acts at DNA breaks. Without Apollo, leading-end telomeres undergo fusion, which, as demonstrated here, is mediated by alternative end joining. Here, we show that DNA-PK and TRF2 coordinate the repression of MRN at blunt mouse telomeres. DNA-PK represses an MRN-dependent long-range resection, while the endonuclease activity of MRN-CtIP, which could cleave DNA-PK off of blunt telomere ends, is inhibited in vitro and in vivo by the iDDR of TRF2. AlphaFold-Multimer predicts a conserved association of the iDDR with Rad50, potentially interfering with CtIP binding and MRN endonuclease activation. We propose that repression of MRN-mediated resection is a conserved aspect of telomere maintenance and represents an ancient feature of DNA-PK and the iDDR.

RevDate: 2023-08-31

Liu M, Lan Y, Zhang H, et al (2023)

Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study.

Melanoma research pii:00008390-990000000-00095 [Epub ahead of print].

The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.

RevDate: 2023-08-30

Greenland JR, Guo R, Lee S, et al (2023)

Short Airway Telomeres are Associated with Primary Graft Dysfunction and Chronic Lung Allograft Dysfunction.

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation pii:S1053-2498(23)02003-X [Epub ahead of print].

Primary graft dysfunction (PGD) is a major risk factor for chronic lung allograft dysfunction (CLAD) following lung transplantation, but the mechanisms linking these pathologies are poorly understood. We hypothesized that the replicative stress induced by PGD would lead to erosion of telomeres, and that this telomere dysfunction could potentiate CLAD. In a longitudinal cohort of 72 lung transplant recipients with >6 years median follow-up time, we assessed tissue telomere length, PGD grade, and freedom from CLAD. Epithelial telomere length and fibrosis-associated gene expression were assessed on endobronchial biopsies taken at 2 - 4 weeks post-transplant by TeloFISH assay and nanoString digital RNA counting. Negative-binomial mixed-effects and Cox-proportional hazards models accounted for TeloFISH staining batch effects and subject characteristics including donor age. Increasing grade of PGD severity was associated with shorter airway epithelial telomere lengths (P = 0.01). Transcriptomic analysis of fibrosis-associated genes showed alteration in fibrotic pathways in airway tissue recovering from PGD, while telomere dysfunction was associated with inflammation and impaired remodeling. Shorter tissue telomere length was in turn associated with increased CLAD risk, with a hazard ratio of 1.89 (95% CI 1.16 - 3.06) per standard deviation decrease in airway telomere length, after adjusting for subject characteristics. PGD may accelerate telomere dysfunction, potentiating immune responses and dysregulated repair. Epithelial cell telomere dysfunction may represent one of several mechanisms linking PGD to CLAD.

RevDate: 2023-08-30

Li H, R Durbin (2023)

Genome assembly in the telomere-to-telomere era.


De novo assembly is the process of reconstructing the genome sequence of an organism from sequencing reads. Genome sequences are essential to biology, and assembly has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best but technological advances in long-read sequencing now enable near complete chromosome-level assembly, also known as telomere-to-telomere assembly, for many organisms. Here we review recent progress on assembly algorithms and protocols. We focus on how to derive near telomere-to-telomere assemblies and discuss potential future developments.

RevDate: 2023-08-29

Häussler S, Ghaffari MH, Seibt K, et al (2023)

Blood and liver telomere length, mitochondrial DNA copy number, and hepatic gene expression of mitochondrial dynamics in mid-lactation cows supplemented with L-carnitine under systemic inflammation.

Journal of dairy science pii:S0022-0302(23)00569-6 [Epub ahead of print].

The current study was conducted to examine the effect of L-carnitine supplementation on telomere length and mitochondrial DNA copy number (mtDNAcn) per cell in mid-lactation cows challenged by lipopolysaccharide (LPS) in blood and liver. The mRNA abundance of 31 genes related to inflammation, oxidative stress, and the corresponding stress response mechanisms, the mitochondrial quality control and the protein import system, as well as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, were assessed using microfluidics integrated fluidic circuit chips (96.96 dynamic arrays). Besides comparing the responses in cows with or without L-carnitine, our objectives were to characterize the oxidative and inflammatory status by assessing the circulating concentration of lactoferrin (Lf), haptoglobin (Hp), fibrinogen, derivates of reactive oxygen metabolites (dROM), and arylesterase activity (AEA), and to extend the measurement of Lf and Hp to milk. Pluriparous Holstein cows were assigned to either a control group (CON, n = 26) or an L-carnitine supplemented group (CAR; 25 g L-carnitine/cow/d; d 42 ante partum to d 126 postpartum (pp), n = 27). On d 111 pp, each cow was injected intravenously with LPS (Escherichia coli O111: B4, 0.5 µg/kg). The mRNA abundance was examined in liver biopsies of d -11 and +1 relative to LPS administration. Plasma and milk samples were frequently collected before and after the challenge. After LPS administration, circulating plasma fibrinogen and serum dROM concentrations increased, whereas AEA decreased. Moreover, serum P4 initially increased by 3 h after LPS administration and declined thereafter irrespective of grouping. The Lf concentrations increased in both groups after LPS administration, with the CAR group showing greater concentrations in serum and milk than the CON group. After LPS administration, telomere length in blood increased, whereas mtDNAcn per cell decreased; however, both remained unaffected in liver. For mitochondrial protein import genes, the hepatic mRNA abundance of the translocase of the mitochondrial inner membrane (TIM)-17B was increased in CAR cows. Moreover, TIM23 increased in both groups after LPS administration. Regarding the mRNA abundance of genes related to stress response mechanisms, 7 out of 14 genes showed group × time interactions, indicating a (local) protective effect due to the dietary L-carnitine supplementation against oxidative stress in mid-lactating dairy cows. For mtDNAcn and telomere length, the effects of the LPS-induced inflammation were more pronounced than the dietary supplementation of L-carnitine. Dietary L-carnitine supplementation affected the response to LPS primarily by altering mitochondrial dynamics. Regarding mRNA abundance of genes related to the mitochondrial protein import system, the inner mitochondrial membrane translocase (TIM complex) seemed to be more sensitive to dietary L-carnitine than the outer mitochondrial membrane translocase (TOM complex).

RevDate: 2023-08-27

Wang L, Zhang M, Li M, et al (2023)

A telomere-to-telomere gap-free assembly of soybean genome.

Molecular plant pii:S1674-2052(23)00247-2 [Epub ahead of print].

RevDate: 2023-08-29
CmpDate: 2023-08-28

Igoshin AV, Yudin NS, Romashov GA, et al (2023)

A Multibreed Genome-Wide Association Study for Cattle Leukocyte Telomere Length.

Genes, 14(8):.

Telomeres are terminal DNA regions of chromosomes that prevent chromosomal fusion and degradation during cell division. In cattle, leukocyte telomere length (LTL) is associated with longevity, productive lifespan, and disease susceptibility. However, the genetic basis of LTL in this species is less studied than in humans. In this study, we utilized the whole-genome resequencing data of 239 animals from 17 cattle breeds for computational leukocyte telomere length estimation and subsequent genome-wide association study of LTL. As a result, we identified 42 significant SNPs, of which eight were found in seven genes (EXOC6B, PTPRD, RPS6KC1, NSL1, AGBL1, ENSBTAG00000052188, and GPC1) when using covariates for two major breed groups (Turano-Mongolian and European). Association analysis with covariates for breed effect detected 63 SNPs, including 13 in five genes (EXOC6B, PTPRD, RPS6KC1, ENSBTAG00000040318, and NELL1). The PTPRD gene, demonstrating the top signal in analysis with breed effect, was previously associated with leukocyte telomere length in cattle and likely is involved in the mechanism of alternative lengthening of telomeres. The single nucleotide variants found could be tested for marker-assisted selection to improve telomere-length-associated traits.

RevDate: 2023-08-24

Ha SJ, Kwag E, Kim S, et al (2023)

Effect of Traditional Korean Medicine Oncotherapy on the Survival, Quality of Life, and Telomere Length: A Prospective Cohort Study.

Integrative cancer therapies, 22:15347354231154267.

A 4-year prospective cohort study on patients with lung, gastric, hepatic, colorectal, breast, uterine, and ovarian cancer was conducted at the East-West Cancer Center (EWCC) of Daejeon Korean Medicine Hospital in Daejeon, Korea. We divided patients into 2 groups based on how long they had been receiving TKM oncotherapy and compared event-free survival (EFS), telomere length change, and quality of life (QoL). The study collected data on 83 patients from October 2016 to June 2020 and discovered no statistical differences in EFS based on the duration of TKM oncotherapy. In the analysis of changes in QoL outcomes, there were no statistically significant group differences between the groups. After controlling for covariates that could affect telomere length, the long-term TKM oncotherapy group had a higher daily telomere attrition rate. The study of the relationship between telomere length and prognostic factors discovered that patients with advanced N stage at the time of diagnosis and who had previously received radiotherapy had shorter telomere length. When examining associations between SNP genotype and percentile score of telomere length, this study was able to confirm an association between telomere length and rs4387287. This study is significant because it is the first to assess the effects of TKM oncotherapy and investigate telomere length-related factors. To assess the effects of TKM oncotherapy on cancer patients' survival and QoL, a longer-term observational study with a larger sample size is required.

RevDate: 2023-08-23

Dupoué A, Mello DF, Trevisan R, et al (2023)

Intertidal limits shape covariation between metabolic plasticity, oxidative stress and telomere dynamics in Pacific oyster (Crassostrea gigas).

Marine environmental research, 191:106149 pii:S0141-1136(23)00277-5 [Epub ahead of print].

In intertidal zones, species such as sessile shellfish exhibit extended phenotypic plasticity to face rapid environmental changes, but whether frequent exposure to intertidal limits of the distribution range impose physiological costs for the animal remains elusive. Here, we explored how phenotypic plasticity varied along foreshore range at multiple organization levels, from molecular to cellular and whole organism acclimatization, in the Pacific oyster (Crassostrea gigas). We exposed 7-month-old individuals for up to 16 months to three foreshore levels covering the vertical range for this species, representing 20, 50 and 80% of the time spent submerged monthly. Individuals at the upper range limit produced energy more efficiently, as seen by steeper metabolic reactive norms and unaltered ATP levels despite reduced mitochondrial density. By spending most of their time emerged, oysters mounted an antioxidant shielding concomitant with lower levels of pro-oxidant proteins and postponed age-related telomere attrition. Instead, individuals exposed at the lower limit range near subtidal conditions showed lower energy efficiencies, greater oxidative stress and shorter telomere length. These results unraveled the extended acclimatization strategies and the physiological costs of living too fast in subtidal conditions for an intertidal species.

RevDate: 2023-08-23

Frydrychová RČ, Konopová B, Peska V, et al (2023)

Telomeres and telomerase: active but complex players in life-history decisions.

Biogerontology [Epub ahead of print].

Studies on human telomeres have established that telomeres exert a significant influence on lifespan and health of organisms. However, recent research has indicated that the original idea that telomeres affect lifespan in a universal and central manner across all eukaryotic species is an oversimplification. Indeed, findings from a variety of animal species revealed that the role of telomere biology in aging is more subtle and intricate than previously recognized. Here, we show how telomere biology varies depending on the taxon. We also show how telomere biology corresponds to basic life history traits and affects the life table of a species and investments in growth, body size, reproduction, and lifespan; telomeres are hypothesized to shape evolutionary perspectives for species in an active but complex manner. Our evaluation is based on telomere biology data from many examples from throughout the animal kingdom that vary according to the degree of organismal complexity and life history strategies.

RevDate: 2023-08-24
CmpDate: 2023-08-24

Liu C, Ding K, Abdul M, et al (2023)

The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis.

BMC anesthesiology, 23(1):284.

BACKGROUND: Cognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases.

METHODS: For this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score ≤ -1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL.

RESULTS: Overall, 20.4% [40/196; 95% confidence interval (CI), 14.7-26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01-54.84; P < 0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29-46.24; P < 0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722-0.859; P < 0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%.

CONCLUSIONS: In summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.

RevDate: 2023-08-22

Eastwood JR, Dupoué A, Verhulst S, et al (2023)

Cool, dry nights and short heatwaves during growth result in longer telomeres in temperate songbird nestlings.

Molecular ecology [Epub ahead of print].

Exposure to rising sublethal temperatures can affect development and somatic condition, and thereby Darwinian fitness. In the context of climate warming, these changes could have implications for population viability, but they can be subtle and consequently difficult to quantify. Using telomere length (TL) as a known biomarker of somatic condition in early life, we investigated the impact of pre-hatching and nestling climate on six cohorts of wild nestling superb fairy wrens (Malurus cyaneus) in temperate south-eastern Australia. Models incorporating only climate information from the nestling phase were best supported compared to those including the (pre-)laying to incubation phase (previously shown to affect mass) or both phases combined. This implies that nestling TL is most sensitive to ambient climate in the nestling phase. The top model showed a negative relationship between early-life TL and nestling mean daily minimum temperature when rainfall was low which gradually became positive with increasing rainfall. In addition, there was a positive relationship between TL and the frequency of hot days (daily maximum temperature ≥35°C), although these temperatures were rare and short-term. Including other pre-hatching and nestling period, climate variables (e.g., mean daily maximum temperature and mean diurnal temperature variability) did not improve the prediction of nestling TL. Overall, our results suggest that cooler nights when conditions are dry and short-term temperature spikes above 35°C during development are conducive for somatic maintenance. While these findings indicate a potential pathway for climate warming to impact wildlife fitness, they emphasize the need to elucidate the mechanisms underlying these complex associations.

RevDate: 2023-08-21

Lyčka M, Bubeník M, Závodník M, et al (2023)

TeloBase: a community-curated database of telomere sequences across the tree of life.

Nucleic acids research pii:7246534 [Epub ahead of print].

Discoveries over the recent decade have demonstrated the unexpected diversity of telomere DNA motifs in nature. However, currently available resources, 'Telomerase database' and 'Plant rDNA database', contain just fragments of all relevant literature published over decades of telomere research as they have a different primary focus and limited updates. To fill this gap, we gathered data about telomere DNA sequences from a thorough literature screen as well as by analysing publicly available NGS data, and we created TeloBase ( as a comprehensive database of information about telomere motif diversity. TeloBase is supplemented by internal taxonomy utilizing popular on-line taxonomic resources that enables in-house data filtration and graphical visualisation of telomere DNA evolutionary dynamics in the form of heat tree plots. TeloBase avoids overreliance on administrators for future data updates by having a simple form and community-curation system for application and approval, respectively, of new telomere sequences by users, which should ensure timeliness of the database and topicality. To demonstrate TeloBase utility, we examined telomere motif diversity in species from the fungal genus Aspergillus, and discovered (TTTATTAGGG)n sequence as a putative telomere motif in the plant family Chrysobalanaceae. This was bioinformatically confirmed by analysing template regions of identified telomerase RNAs.

RevDate: 2023-08-23

Gorsi HS, Gallardo-Rios M, S Savaşan (2023)

Short telomere length in autoimmune neutropenia of childhood: A mere coincidence or an association?.

EJHaem, 4(3):827-828.

RevDate: 2023-08-22
CmpDate: 2023-08-22

Han X, Wu T, CY Liu (2023)

Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes.

Frontiers in endocrinology, 14:1225600.

BACKGROUND: Numerous observational studies have revealed a correlation between telomere length (TL) and adverse pregnancy outcomes (APOs). However, the impacts of TL on APOs are still unclear.

METHODS: Mendelian randomization (MR) was carried out using summary data from genome-wide association studies (GWAS). Inverse variance weighted (IVW) was employed as the primary analysis to explore the causal relationship between TL and APOs. The exposure data came from a GWAS dataset of IEU analysis of the United Kingdom Biobank phenotypes consisting of 472,174 European participants. Summary-level data for five APOs were obtained from the GWAS datasets of the FinnGen consortium. We also performed multivariate MR (MVMR), adjusting for smoking, alcohol intake, body mass index (BMI), and number of live births. In addition, we conducted a series of rigorous analyses to further examine the validity of our MR findings.

RESULTS: After Bonferroni correction and rigorous quality control, univariable MR (UVMR) demonstrated that a shorter TL was significantly associated with an increased risk of spontaneous abortion (SA) (odds ratio [OR]: 0.815; 95% confidence interval [CI]: 0.714-0.930; P = 0.002) and preterm birth (PTB) (OR: 0.758; 95% CI: 0.632-0.908; P = 0.003) in the IVW model. There was a nominally significant relationship between TL and preeclampsia (PE) in the IVW model (OR: 0.799; 95% CI: 0.651-0.979; P = 0.031). However, no significant association was found between TL and gestational diabetes mellitus (GDM) (OR: 0.950; 95% CI: 0.804-1.122; P = 0.543) or fetal growth restriction (FGR) (OR: 1.187; 95% CI: 0.901-1.565; P = 0.223) among the five statistical models. Furthermore, we did not find a significant causal effect of APOs on TL in the reverse MR analysis. MVMR analysis showed that the causal effects of TL on SA remained significant after accounting for smoking, alcohol intake, BMI, and number of live births.

CONCLUSION: Our MR study provides robust evidence that shorter telomeres were associated with an increased risk of SA. Further work is necessary to investigate the potential mechanisms. UVMR and MVMR findings showed limited evidence that TL affects the risk of PTB, PE, GDM, and FGR, illustrating that the outcomes of previous observational studies may have been confounded.

RevDate: 2023-08-20

Mo W, Shu Y, Liu B, et al (2023)

Single-molecule targeted accessibility and methylation sequencing of centromeres, telomeres and rDNAs in Arabidopsis.

Nature plants [Epub ahead of print].

The short read-length of next-generation sequencing makes it challenging to characterize highly repetitive regions (HRRs) such as centromeres, telomeres and ribosomal DNAs. Based on recent strategies that combined long-read sequencing and exogenous enzymatic labelling of open chromatin, we developed single-molecule targeted accessibility and methylation sequencing (STAM-seq) in plants by further integrating nanopore adaptive sampling to investigate the HRRs in wild-type Arabidopsis and DNA methylation mutants that are defective in CG- or non-CG methylation. We found that CEN180 repeats show higher chromatin accessibility and lower DNA methylation on their forward strand, individual rDNA units show a negative correlation between their DNA methylation and accessibility, and both accessibility and CHH methylation levels are lower at telomere compared to adjacent subtelomeric region. Moreover, DNA methylation-deficient mutants showed increased chromatin accessibility at HRRs, consistent with the role of DNA methylation in maintaining heterochromatic status in plants. STAM-seq can be applied to study accessibility and methylation of repetitive sequences across diverse plant species.

RevDate: 2023-08-20

Stylianakis E, Chan JPK, Law PP, et al (2023)

Mouse HP1γ regulates TRF1 expression and telomere stability.

Life sciences pii:S0024-3205(23)00665-3 [Epub ahead of print].

AIMS: Telomeric repeat-containing RNAs are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the heterochromatin protein 1 (HP1) protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed human and mouse genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance.

MAIN METHODS: We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblasts (MEFs). We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA immunoprecipitation (DRIP).

KEY FINDINGS: Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNA-RNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X.

SIGNIFICANCE: Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

RevDate: 2023-08-20

Zhang D, Chen X, Huang K, et al (2023)

Urinary essential and toxic metal mixtures, and type 2 diabetes mellitus: Telomere shortening as an intermediary factor?.

Journal of hazardous materials, 459:132329 pii:S0304-3894(23)01612-6 [Epub ahead of print].

The joint effect of metal mixtures on telomere function and type 2 diabetes mellitus (T2DM) is unclear. This large-scale cross-sectional study sought to assess the role of telomere length (TL) in the relationship between urinary essential and toxic metal mixtures, and T2DM in 7410 Chinese adults ≥ 60 years of age. Essential (Cr, Cu, Zn, Se) and non-essential metals (V, Al, Sb, Sn, Cd, Pb) in urine samples were quantified, while leukocyte TL was measured from blood samples. Restricted cubic splines regression showed nonlinear relationships between single metal and T2DM, and between TL and T2DM. Bayesian kernel machine regression and quantile-based g-computation showed that the overall status of urinary metals was positively associated with risk of developing T2DM, which was mainly explained by exposure to Pb, Cd, and Sb, excessive Se intake, and high excretion of Zn. Mediation analyses showed that shortened TL mediated 27.9% of the overall positive effect of metal exposure on T2DM, and this mediation was mainly explained by toxic metal exposure and excessive Se intake. Tobacco smoke exposure, extensive cooking at home, and black tea consumption were found to be important contributors of toxic metal exposures. Further studies are needed to explore the recommended Zn dosage for T2DM patients at different stages, which may ameliorate pancreatic senescence and glycemic progression.

RevDate: 2023-08-19

Zhang Y, Zhu Y, Ye M, et al (2023)

Telomere length and its association with systemic lupus erythematosus in an Asian population: A Mendelian randomization study.

Lupus [Epub ahead of print].

OBJECTIVES: To investigate whether shorter telomere length is a causal risk factor for systemic lupus erythematosus (SLE) in the Asian population.

METHODS: We applied the two-sample Mendelian randomization (MR) method to the pooled statistics from a genome-wide association study (GWAS) of 6,707 SLE cases and 16,047 controls. We selected nine single-nucleotide polymorphisms (SNPs) with genome-wide significance as instrumental variables for telomere length. The main analysis was carried out by the random-effects inverse-variance weighted (IVW) method. Horizontal pleiotropy was evaluated by the intercept of MR-Egger regression.

RESULTS: A potentially causal relationship between longer genetically predicted telomere length and increased risk of systemic lupus erythematosus (OR = 1.72, 95%CI: 1.21, 2.46, p = 0.01) was observed. The MR-Egger regression demonstrated an intercept proximal to zero (intercept = 0.017, p = 0.69), which does not provide evidence of the presence of horizontal pleiotropy.

CONCLUSIONS: Our findings provided evidence supporting a potential causal relationship between longer telomere length and increased risk of systemic lupus erythematosus.

RevDate: 2023-08-18

He Y, Chu Y, Guo S, et al (2023)

T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.

Genomics, proteomics & bioinformatics pii:S1672-0229(23)00100-6 [Epub ahead of print].

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere version-T2T-CHM13-reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. To provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we have assembled the genome of a male Han Chinese individual, T2T-YAO, which includes telomere-to-telomere assemblies of all the 22+X+M and 22+Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼330 Mb exclusive sequences, ∼3100 unique genes, and tens of thousands of nucleotide and structural variations as compared to CHM13, highlighting the necessity of population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

RevDate: 2023-08-18

Rinne GR, Carroll JE, Guardino CM, et al (2023)

Parental preconception posttraumatic stress symptoms and maternal prenatal inflammation prospectively predict shorter telomere length in children.

Psychosomatic medicine pii:00006842-990000000-00153 [Epub ahead of print].

OBJECTIVE: Parental trauma exposure and trauma-related distress can increase risk for adverse health outcomes in offspring, but the pathways implicated in intergenerational transmission are not fully explicated. Accelerated biological aging may be one mechanism underlying less favorable health in trauma-exposed individuals and their offspring. This study examines associations of preconception maternal and paternal posttraumatic stress disorder (PTSD) symptoms with child telomere length, and maternal prenatal C-reactive protein (CRP) as a biological mechanism.

METHODS: Mothers (n = 127) and a subset of the fathers (n = 84) reported on PTSD symptoms before conception. Mothers provided blood spots in the second and third trimester that were assayed for CRP. At age 4, children provided buccal cells for measurement of telomere length. Models adjusted for parental age, socioeconomic status, maternal pre-pregnancy BMI, child biological sex, and child age.

RESULTS: Mothers' PTSD symptoms were significantly associated with shorter child telomere length (β = -0.22, SE = 0.10, p = .023). Fathers' PTSD symptoms were also inversely associated with child telomere length (β = -0.21, SE = 0.11), though nonsignificant (p = .065). There was no significant indirect effect of mothers' PTSD symptoms on child telomere length through CRP in pregnancy, but higher second trimester CRP was significantly associated with shorter child telomere length (β = -0.35, SE = 0.18, p = .048).

CONCLUSIONS: Maternal symptoms of PTSD prior to conception and second trimester inflammation were associated with shorter telomere length in offspring in early childhood, independent of covariates. Findings indicate intergenerational transmission of parental trauma may occur in part through accelerated biological aging processes and provide further evidence that prenatal pro-inflammatory processes program child telomere length.Open Science Framework Pre-registration:

RevDate: 2023-08-18

Luo X, Ruan Z, L Liu (2023)

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study.

Epilepsia open [Epub ahead of print].

OBJECTIVE: Observational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis.

METHODS: We performed a bidirectional two-sample MR analysis using pooled statistics from genome-wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse-variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy.

RESULTS: Our analysis found no evidence of a causal relationship between epilepsy and TL (all P-values > 0.05). The sensitivity analysis confirms the robustness of these results.

SIGNIFICANCE: In summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.

RevDate: 2023-08-18

Huang X (2023)

A Complete Telomere-to-Telomere Assembly Provides New Reference Genome for Rice.

Molecular plant pii:S1674-2052(23)00223-X [Epub ahead of print].

RevDate: 2023-08-17

Zhang D, Adegunsoye A, Oldham JM, et al (2023)

Telomere Length and Immunosuppression in Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Disease.

The European respiratory journal pii:13993003.00441-2023 [Epub ahead of print].

Studies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).A retrospective, multi-centre cohort analysis was performed in fibrotic hypersensitivity pneumonitis, unclassifiable ILD, and connective tissue disease ILD patients from five centres. LTL was measured by qPCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on two-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.The discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL <10th percentile of normal. Fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with LTL <10th percentile experienced reduced survival when exposed to either mycophenolate or azathioprine in the discovery cohort (mortality HR 4.97, 95% CI 2.26-10.92, p<0.001) and replication cohort (mortality HR 4.90, 95% CI 1.74-13.77, p=0.003). Immunosuppressant exposure was not associated with differential survival in patients with LTL ≥10th percentile. There was a significant interaction between LTL <10th percentile and immunosuppressant exposure (Discovery p-interaction=0.013; Replication p-interaction=0.011). Low event rate and prevalence of LTL <10th percentile precluded subgroup analyses for connective tissue disease ILD.Similar to IPF, fibrotic hypersensitivity pneumonitis and unclassifiable ILD patients with age-adjusted LTL <10th percentile may experience reduced survival when exposed to immunosuppression.

RevDate: 2023-08-17

Naudé PJW, Stein DJ, Lin J, et al (2023)

Investigating the association of prenatal psychological adversities with mother and child telomere length and neurodevelopment.

Journal of affective disorders pii:S0165-0327(23)01054-6 [Epub ahead of print].

BACKGROUND: Exposure to prenatal maternal psychological adversities can negatively affect the offspring's developing brain. Shortened telomere length (TL) has been implicated as a mechanism for the transgenerational effects of maternal psychological adversities on offspring. This study aimed to determine associations between prenatal psychological stressors and distress with maternal and early life TL, and associations between maternal, newborn and child TL with neurodevelopmental outcomes at 2 years of age.

METHODS: Follow-up TL was measured in a subgroup of African mothers (n = 138) and their newborns (n = 142) and children (n = 96) at 2-years in the Drakenstein Child Health Study. Prenatal symptoms of depression, distress, intimate partner violence, posttraumatic stress-disorder and childhood trauma were measured at 27 weeks gestation. Neurodevelopment was assessed at 2 years using the Bayley Scales of Infant and Toddler Development III. TLs were measured in whole bloods from mothers and their children at 2-years, and cord bloods in newborns.

RESULTS: Maternal prenatal stressors and distress were not significantly associated with TL in mothers or their children at birth or at 2-years. Furthermore, maternal psychological measures were not associated with early-life attrition of TL. Longer TL in children at 2-years was associated (p = 0.04) with higher motor functioning.

LIMITATIONS: Limited numbers of participants and single time-point psychological measures.

CONCLUSIONS: This study is the first to provide information on the association of early life TL with prenatal psychological adversities and neurodevelopmental outcomes in a population of low-income African mothers and their children.

RevDate: 2023-08-17

Lu ZH, Sun B, Wang YX, et al (2023)

Ozone exposure associates with sperm quality indicators: Sperm telomere length as a potential mediating factor.

Journal of hazardous materials, 459:132292 pii:S0304-3894(23)01575-3 [Epub ahead of print].

Evidence linking O3 exposure and human semen quality is limited and conflicting and the mechanism underlying the association remains unclear. Therefore, we investigated the associations between ambient O3 exposure and sperm quality parameters and explored the mediating role of sperm mitochondrial DNA copy number (mtDNAcn) and sperm telomere length (STL) among 1068 potential sperm donors who provided 5002 repeated semen samples over approximately 90 days. We found that every 10 μg/m[3] increase in O3 exposure was associated with a decrease in STL, sperm concentration, total count, total motile sperm number, and semen volume. However, O3 exposure was associated with increased total motility and progressive motility. The association for sperm quality parameters was stronger when exposure was measured at spermatogenesis stages I and II. For STL, the strongest association was observed when exposure was measured at spermatogenesis stage II. Additionally, we found that approximately 9% and 8% of the association between O3 exposure and sperm concentration and count was mediated by STL, respectively. In summary, our findings suggest that O3 pollution may affect sperm telomere length, eventually leading to reduced semen quality.

RevDate: 2023-08-17

Vellingiri B, Balasubramani K, Iyer M, et al (2023)

Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?.

Advanced biology [Epub ahead of print].

Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.

RevDate: 2023-08-17

Chen H, Liang W, Zheng W, et al (2023)

A novel telomere-related gene prognostic signature for survival and drug treatment efficiency prediction in lung adenocarcinoma.

Aging, 15: pii:204877 [Epub ahead of print].

OBJECTIVE: Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency.

METHODS: A total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups.

RESULTS: A total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy.

CONCLUSION: This study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy.

RevDate: 2023-08-17

Zhu S, Yang M, Wang T, et al (2023)

Causal relationships between telomere length and liver disease: a Mendelian randomization study.

Frontiers in genetics, 14:1164024.

Background: Leukocyte telomere length and hepatic disorders have been linked in various research studies, although their causative association has not been clarified. This study investigated the causal relationship between the length of telomeres on peripheral blood leukocytes and certain liver disorders. Methods: Mendelian randomization (MR) analysis was used to examine the relationship between leukocyte telomere length and risk of liver disease using the publicly accessible worldwide gene-wide association study (GWAS) database. The weighted mode, weighted median, and inverse variance weighted (IVW) methods were employed as supplements to the IVW approach, which is the main analytical method. Results: Leukocytes with longer telomeres may have a lower risk of developing cirrhosis [OR = 0.645 (0.524, 0.795), p = 3.977E-05] and a higher chance of developing benign liver tumors [OR = 3.087 (1.721, 5.539), p = 1.567E-04]. There was no direct link between telomere length and fatty liver, hepatic fibrosis, or liver cancer. Our findings in the replication analysis agreed with those of the previous studies. Conclusion: Further research is needed to examine the mechanisms underlying the probable causal association between the length of leukocyte telomeres and cirrhosis and benign liver cancer.

RevDate: 2023-08-16

He Q, CJ Lim (2023)

Models for human telomere C-strand fill-in by CST-Polα-primase.

Trends in biochemical sciences pii:S0968-0004(23)00174-3 [Epub ahead of print].

Telomere maintenance is essential for the genome integrity of eukaryotes, and this function is underpinned by the two-step telomeric DNA synthesis process: telomere G-overhang extension by telomerase and complementary strand fill-in by DNA polymerase alpha-primase (polα-primase). Compared to the telomerase step, the telomere C-strand fill-in mechanism is less understood. Recent studies have provided new insights into how telomeric single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) and polα-primase coordinate to synthesize the telomeric C-strand for telomere overhang fill-in. Cryogenic electron microscopy (cryo-EM) structures of CST-polα-primase complexes have provided additional insights into how they assemble at telomeric templates and de novo synthesize the telomere C-strand. In this review, we discuss how these latest findings coalesce with existing understanding to develop a human telomere C-strand fill-in mechanism model.

RevDate: 2023-08-14

Brown RL, Epel EE, Lin J, et al (2023)

Associations between klotho and telomere biology in high stress caregivers.

Aging, 15: pii:204961 [Epub ahead of print].

Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.

RevDate: 2023-08-14

Lee J, Lee J, Sohn EJ, et al (2023)

Extrachromosomal Telomeres Derived from Excessive Strand Displacements.

bioRxiv : the preprint server for biology pii:2023.07.31.551186.

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance mechanism mediated by break-induced replication (BIR), evident in approximately 15% of human cancers. A characteristic feature of ALT cancers is the presence of C-circles, circular single-stranded telomeric DNAs composed of C-rich sequences. Despite the fact that extrachromosomal C-rich single-stranded DNAs (ssDNAs), unique to ALT cells, are considered potential precursors of C-circles, their generation process remains undefined. Here, we introduce a highly sensitive method to detect single stranded telomeric DNA, called 4SET (Strand-Specific Southern-blot for Single-stranded Extrachromosomal Telomeres) assay. Utilizing 4SET, we are able to capture C-rich single stranded DNAs are near 500 bp in size. Both C-rich ssDNAs and C-circles are abundant in cytoplasmic fraction which supports the idea that C-rich ssDNAs may indeed precede C-circles. We also found that C-rich ssDNAs originate during Okazaki fragment processing in lagging strands. The generation of C-rich ssDNA requires CST-PP (CTC1/STN1/TEN1-PRIMASE-Polymerase alpha)-complex mediated priming of the C-strand synthesis and subsequent excessive strand displacement of C-rich strand through DNA Polymerase delta and BLM helicase. Our work proposes a new model for the generation of C-rich ssDNAs and C-circles that are indicative of the presence of ALT pathway.

RevDate: 2023-08-14
CmpDate: 2023-08-14

Yamaguchi I, Ikawa K, Takimiya N, et al (2023)

Tetraphenylethene Derivatives Bearing Alkylammonium Substituents: Synthesis, Chemical Properties, and Application as BSA, Telomere DNA, and Hydroxyl Radical Sensors.

Molecules (Basel, Switzerland), 28(15):.

Tetraphenylethene derivatives (TPEs) are used as luminescence probes for the detection of metal ions and biomolecules. These sensors function by monitoring the increase in the photoluminescence (PL) intensity of the TPEs resulting from aggregation-induced emission (AIE) upon interaction with the analytes. The AIE behavior of the sensors was investigated by measuring their PL. In this study, PL, PL lifetime, and confocal laser scanning microscopy measurements were carried out as part of our in-depth investigation of AIE behavior of TPEs for the detection of biomolecules and radical species. We used 1,1,2,2-tetrakis(4-((trimethylammonium)alkoxy)phenyl)tetraphenylethene tetrabromide (TPE-C(m)N[+]Me3Br[-], m = 2, 4, and 6, where m denotes the number of methylene groups in the alkyl chain) and TPE-C(m)N[+]Me3TCNQ[-•] (TCNQ[-•] is the 7,7',8,8'-tetracyanoquinodimethane anion radical) as luminescent probes for the detection of bovine serum albumin (BSA), DNA, and the hydroxyl radical ([•]OH) generated from Fenton's reagent. The sensing performance of TPE-C(m)N[+]Me3Br[-] for BSA and DNA was found to depend on the length of the alkyl chains (m). UV-vis and PL measurements revealed that the responses of TPE-C(m)N[+]Me3Br[-] and TPE-C(4)N[+]TCNQ[-•] to Fenton's reagent depended on the solvent. The electrochemical properties of the TPE derivatives prepared in this study were additionally investigated via cyclic voltammetry.

RevDate: 2023-08-14
CmpDate: 2023-08-14

Li XH, Sun MH, Jiang WJ, et al (2023)

ZSCAN4 Regulates Zygotic Genome Activation and Telomere Elongation in Porcine Parthenogenetic Embryos.

International journal of molecular sciences, 24(15):.

Zinc finger and SCAN domain-containing 4 (ZSCAN4), a DNA-binding protein, maintains telomere length and plays a key role in critical aspects of mouse embryonic stem cells, including maintaining genomic stability and defying cellular senescence. However, the effect of ZSCAN4 in porcine parthenogenetic embryos remains unclear. To investigate the function of ZSCAN4 and the underlying mechanism in porcine embryo development, ZSCAN4 was knocked down via dsRNA injection in the one-cell stage. ZSCAN4 was highly expressed in the four- and five- to eight-cell stages in porcine embryos. The percentage of four-cell stage embryos, five- to eight-cell stage embryos, and blastocysts was lower in the ZSCAN4 knockdown group than in the control group. Notably, depletion of ZSCAN4 induced the protein expression of DNMT1 and 5-Methylcytosine (5mC, a methylated form of the DNA base cytosine) in the four-cell stage. The H3K27ac level and ZGA genes expression decreased following ZSCAN4 knockdown. Furthermore, ZSCAN4 knockdown led to DNA damage and shortened telomere compared with the control. Additionally, DNMT1-dsRNA was injected to reduce DNA hypermethylation in ZSCAN4 knockdown embryos. DNMT1 knockdown rescued telomere shortening and developmental defects caused by ZSCAN4 knockdown. In conclusion, ZSCAN4 is involved in the regulation of transcriptional activity and is essential for maintaining telomere length by regulating DNMT1 expression in porcine ZGA.

RevDate: 2023-08-11

Ye Q, Apsley AT, Etzel L, et al (2023)

Telomere length and chronological age across the human lifespan: a systematic review and meta-analysis of 414 study samples including 743,019 individuals.

Ageing research reviews pii:S1568-1637(23)00190-3 [Epub ahead of print].

Telomere attrition is a proposed hallmark of aging. To evaluate the association of telomere length (TL) with chronological age across the human lifespan, we conducted a systematic review and meta-analysis of 414 study samples comprising 743,019 individuals aged 0 to 112 years. We examined both cross-sectional and longitudinal data, and evaluated the impact of various biological and methodological factors including sex, health status, tissue types, DNA extraction procedures, and TL measurement methods. The pooled corrected correlation between TL and age from cross-sectional samples was -0.19 (95%CI: -0.22 to -0.15), which weakened with increased chronological age (β=0.003, p<0.001). Z-score change rates of TL across the lifespan showed a gradual decrease in shortening rate until around age 50 and remained at a relatively stable rate towards the elderly period. A greater attrition rate was observed in longitudinal than cross-sectional evaluations. For TL measured in base pairs, the median change rate of TL was -23 bp/year in cross-sectional samples and -38 bp/year in longitudinal samples. Methodological factors including TL measurement methods and tissue types impacted the TL-age correlation, while sex or disease status did not. This meta-analysis revealed the non-linear shortening trend of TL across the human lifespan and provides a reference value for future studies. Results also highlight the importance of methodological considerations when using TL as an aging biomarker.

RevDate: 2023-08-11

Nose D, Shiga Y, Takahashi RU, et al (2023)

Association Between Telomere G-Tail Length and Coronary Artery Disease or Statin Treatment in Patients With Cardiovascular Risks - A Cross-Sectional Study.

Circulation reports, 5(8):338-347.

Background: The utility of telomere G-tail length to predict coronary artery disease (CAD) remains controversial. CAD results from coronary artery narrowing due to cholesterol and lipid accumulation, augmented by inflammatory cells and other factors. This study explored the significance of telomere G-tail length in suspected CAD patients. Methods and Results: In all, 95 patients with suspected CAD or ≥1 cardiac risk factor underwent coronary computed tomography angiography (CCTA). We measured leukocyte telomere length and G-tail length using a hybrid protection method, and diagnosed the presence of CAD using CCTA. Associations between G-tail length and the presence of CAD, the number of stenosed coronary arteries, and brachial-ankle pulse wave velocity (baPWV) were analyzed. No significant difference was observed in G-tail length when comparing groups with or without CAD or statin treatment. However, in the non-statin group, G-tail length was significantly shorter in patients with 3-vessel disease compared with 1-vessel disease. Dividing the group using a baPWV of 1,300 cm/s, telomere G-tail length was significantly shorter in the high-risk (baPWV ≥1,300 cm/s) group. Conclusions: The clinical utility of telomere G-tail length as a CAD risk indicator seems limited. There was a trend for longer telomere G-tail length in the statin-treated group. Moreover, telomere G-tail length was reduced in patients at high-risk of cardiovascular events, aligning with the trend of a shortening in telomere G-tail length with CAD severity.

RevDate: 2023-08-10

Takasugi T, Gu P, Liang F, et al (2023)

Pot1b -/- tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation.

Nucleic acids research pii:7240375 [Epub ahead of print].

Malignant cancers must activate telomere maintenance mechanisms to achieve replicative immortality. Mutations in the human Protection of Telomeres 1 (POT1) gene are frequently detected in cancers with abnormally long telomeres, suggesting that the loss of POT1 function disrupts the regulation of telomere length homeostasis to promote telomere elongation. However, our understanding of the mechanisms leading to elongated telomeres remains incomplete. The mouse genome encodes two POT1 proteins, POT1a and POT1b possessing separation of hPOT1 functions. We performed serial transplantation of Pot1b-/- sarcomas to better understand the role of POT1b in regulating telomere length maintenance. While early-generation Pot1b-/- sarcomas initially possessed shortened telomeres, late-generation Pot1b-/- cells display markedly hyper-elongated telomeres that were recognized as damaged DNA by the Replication Protein A (RPA) complex. The RPA-ATR-dependent DNA damage response at telomeres promotes telomerase recruitment to facilitate telomere hyper-elongation. POT1b, but not POT1a, was able to unfold G-quadruplex present in hyper-elongated telomeres to repress the DNA damage response. Our findings demonstrate that the repression of the RPA-ATR DDR is conserved between POT1b and human POT1, suggesting that similar mechanisms may underly the phenotypes observed in human cancers harboring human POT1 mutations.

RevDate: 2023-08-11

Teng Y, Huang DQ, Li RX, et al (2023)

Association Between Telomere Length and Risk of Lung Cancer in an Asian Population: A Mendelian Randomization Study.

World journal of oncology, 14(4):277-284.

BACKGROUND: Several traditional observational studies and Mendelian randomization (MR) studies have indicated an association between leukocyte telomere length (LTL) and the risk of lung cancer in the European population. However, the results in the Asian population are still unclear. The objective was to reveal the genetic causal association between LTL and the risk of lung cancer in the Asian population.

METHODS: We conducted a two-sample MR analysis using summary statistics. Instrumental variables (IVs) were obtained from the genome-wide association studies (GWAS) of LTL (n = 23,096) and lung cancer (n = 212,453) of Asian ancestry. We applied the random-effects inverse-variance weighted (IVW) model as the main method. As well, several other models were performed as complementary methods to assess the impact of potential MR assumption violations, including MR-Egger regression, weighted median, and weighted mode models.

RESULTS: We included eight single-nucleotide polymorphisms (SNPs) as IVs for LTL and found that LTL was significantly associated with the risk of lung cancer in the IVW model (odds ratio (OR): 1.60; 95% confidence interval (CI): 1.31 - 1.97; P = 5.96 × 10[-6]), which was in line with the results in the weighted median and weighted mode models. However, the relationship was not statistically significant in the MR-Egger regression model (OR: 1.44; 95% CI: 0.92 - 2.26; P = 0.160). Sensitivity analyses indicated the robustness of the results.

CONCLUSIONS: This two-sample MR study confirmed that longer telomere length significantly increased the risk of lung cancer in the Asian population, which was in accord with findings in the Western population.

RevDate: 2023-05-31
CmpDate: 2023-05-29

Hill C, Duffy S, Kettyle LM, et al (2023)

Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes.

Genes, 14(5):.

Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case-control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case-control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10[-6]). Telomere length was also significantly reduced (p = 6.6 × 10[-5]) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10[-8]) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.

RevDate: 2023-05-02

Fattahi M, Maghsudlu M, M Hasan Sheikhha (2023)

Is sperm telomere length altered in teratozoospermia specimens? A case-control study.

International journal of reproductive biomedicine, 21(3):229-236.

BACKGROUND: Male factor infertility is a multifactorial defect, and many of its etiologies are unknown. Teratozoospermia is determined by the existence of over 85% morphologically abnormal spermatozoa in semen which are almost incompetent in fertilization function. One of the most novel issues in genetic alterations studies is the variation of sperm telomere lengths (STL) and its collaboration with male infertility. The present study has been focused on STL alterations in teratozoospermia.

OBJECTIVE: Investigation of differences in telomere length of teratozoospermia specimens and sperms with normal parameters.

MATERIALS AND METHODS: In this case-control study, 60 men referred to Arak Fertility Clinic, Markazi province, Iran from November 2017 to February 2018 were categorized into teratozoospermia and normozoospermic groups. Sperm genomic DNA extraction was conducted, and STL were evaluated using quantitative polymerase chain reaction.

RESULTS: Statistical evaluation of relative telomere length was calculated by the ratio of telomere to single-copy gene for teratozoospermia and normal specimens. Results significantly demonstrated that relative telomere length in teratozoospermia samples is nearly 3 times shorter than in normal samples (p > 0.001).

CONCLUSION: Our results represent the reduction of telomeres length in teratozoospermia and suggest that this alteration might be one of the factors contributing to the sperm fertility potential of this kind of specimen. However, defining relevant molecular processes requires further detailed investigations.

RevDate: 2023-07-19
CmpDate: 2023-05-29

Ngo K, Gittens TH, Gonzalez DI, et al (2023)

A comprehensive map of hotspots of de novo telomere addition in Saccharomyces cerevisiae.

Genetics, 224(2):.

Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition (dnTA) on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker's yeast, Saccharomyces cerevisiae, that act as hotspots of dnTA [termed Sites of Repair-associated Telomere Addition (SiRTAs)], but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.

RevDate: 2023-05-12
CmpDate: 2023-05-12

Saradadevi GP, Fultz D, Ramgopal MK, et al (2023)

Structural variation among assembled genomes facilitates development of rapid and low-cost NOR-linked markers and NOR-telomere junction mapping in Arabidopsis.

Plant cell reports, 42(6):1059-1069.

Genome-wide structural variants we identified and new NOR-linked markers we developed would be useful for future genome-wide association studies (GWAS), and for new gene/trait mapping purposes. Bioinformatic alignment of the assembled genomes of Col-0 and Sha ecotypes of Arabidopsis thaliana revealed ~ 13,000 genome-wide structural variants involving simple insertions or deletions and repeat contractions or expansions. Using some of these structural variants, we developed new, rapid, and low-cost PCR-based molecular markers that are genetically linked to the nucleolus organizer regions (NORs). A. thaliana has two NORs, one each on chromosome 2 (NOR2) and chromosome 4 (NOR4). Both NORs are ~ 4 Mb each, and hundreds of 45S ribosomal RNA (rRNA) genes are tandemly arrayed at these loci. Using previously characterized recombinant inbred lines (RILs) derived from Sha x Col-0 crosses, we validated the utility of the newly developed NOR-linked markers in genetically mapping rRNA genes and the associated telomeres to either NOR2 or NOR4. Lastly, we sequenced Sha genome using Oxford Nanopore Technology (ONT) and used the data to obtain sequences of NOR-telomere junctions, and with the help of RILs, we mapped them as new genetic markers to their respective NORs (NOR2-TEL2N and NOR4-TEL4N). The structural variants obtained from this study would serve as valuable data for genome-wide association studies (GWAS), and to rapidly design more genome-wide genetic (molecular) markers for new gene/trait mapping purposes.

RevDate: 2023-05-09
CmpDate: 2023-04-24

Flor-Alemany M, Acosta-Manzano P, Migueles JH, et al (2023)

Influence of an exercise intervention plus an optimal Mediterranean diet adherence during pregnancy on the telomere length of the placenta. The GESTAFIT project.

Placenta, 136:42-45.

We aimed to investigate whether the effects of exercise on placental relative telomere length (RTL) after delivery are modulated by the Mediterranean diet [MD] adherence in 65 pregnant women (control n = 34, exercise n = 31). No differences were found in placental RTL between the exercise and the control groups (p = 0.557). The interaction-term between exercise and MD adherence with placental RTL was significant (p = 0.001). Specifically, women in the exercise group showed longer placental RTL after birth compared to controls (referent group), only for those women with a high MD adherence (mean difference = 0.467, p=0.010). A concurrent-exercise training plus an optimal MD adherence during pregnancy might prevent the placental RTL shortening.

RevDate: 2023-04-11

González-Amor M, Dorado B, V Andrés (2023)

Emerging roles of interferon-stimulated gene-15 in age-related telomere attrition, the DNA damage response, and cardiovascular disease.

Frontiers in cell and developmental biology, 11:1128594.

Population aging and age-related cardiovascular disease (CVD) are becoming increasingly prevalent worldwide, generating a huge medical and socioeconomic burden. The complex regulation of aging and CVD and the interaction between these processes are crucially dependent on cellular stress responses. Interferon-stimulated gene-15 (ISG15) encodes a ubiquitin-like protein expressed in many vertebrate cell types that can be found both free and conjugated to lysine residues of target proteins via a post-translational process termed ISGylation. Deconjugation of ISG15 (deISGylation) is catalyzed by the ubiquitin-specific peptidase 18 (USP18). The ISG15 pathway has mostly been studied in the context of viral and bacterial infections and in cancer. This minireview summarizes current knowledge on the role of ISG15 in age-related telomere shortening, genomic instability, and DNA damage accumulation, as well as in hypertension, diabetes, and obesity, major CVD risk factors prevalent in the elderly population.

RevDate: 2023-07-26
CmpDate: 2023-07-26

Rose AM, Goncalves T, Cunniffe S, et al (2023)

Induction of the alternative lengthening of telomeres pathway by trapping of proteins on DNA.

Nucleic acids research, 51(13):6509-6527.

Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this is achieved through the alternative lengthening of telomeres (ALT) pathway. Whilst loss of ATRX is a near universal feature of ALT-cancers, it is insufficient in isolation. As such, other cellular events must be necessary - but the exact nature of the secondary events has remained elusive. Here, we report that trapping of proteins (such as TOP1, TOP2A and PARP1) on DNA leads to ALT induction in cells lacking ATRX. We demonstrate that protein-trapping chemotherapeutic agents, such as etoposide, camptothecin and talazoparib, induce ALT markers specifically in ATRX-null cells. Further, we show that treatment with G4-stabilising drugs cause an increase in trapped TOP2A levels which leads to ALT induction in ATRX-null cells. This process is MUS81-endonuclease and break-induced replication dependent, suggesting that protein trapping leads to replication fork stalling, with these forks being aberrantly processed in the absence of ATRX. Finally, we show ALT-positive cells harbour a higher load of genome-wide trapped proteins, such as TOP1, and knockdown of TOP1 reduced ALT activity. Taken together, these findings suggest that protein trapping is a fundamental driving force behind ALT-biology in ATRX-deficient malignancies.

RevDate: 2023-03-28
CmpDate: 2023-03-24

D'Aronco G, Ferraro P, Sassano V, et al (2023)

SAMHD1 restricts the deoxyguanosine triphosphate pool contributing to telomere stability in telomerase-positive cells.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37(4):e22883.

SAMHD1 (Sterile alpha motif and histidine/aspartic acid domain-containing protein 1) is a dNTP triphosphohydrolase crucial in the maintenance of balanced cellular dNTP pools, which support genome integrity. In SAMHD1 deficient fibroblasts isolated from Aicardi-Goutières Syndrome (AGS) patients, all four DNA precursors are increased and markedly imbalanced with the largest effect on dGTP, a key player in the modulation of telomerase processivity. Here, we present data showing that SAMHD1, by restricting the dGTP pool, contributes to telomere maintenance in hTERT-immortalized human fibroblasts from AGS patients as well as in telomerase positive cancer cell lines. Only in cells expressing telomerase, the lack of SAMHD1 causes excessive lengthening of telomeres and telomere fragility, whereas primary fibroblasts lacking both SAMHD1 and telomerase enter normally into senescence. Telomere lengthening observed in SAMHD1 deficient but telomerase proficient cells is a gradual process, in accordance with the intrinsic property of telomerase of adding only a few tens of nucleotides for each cycle. Therefore, only a prolonged exposure to high dGTP content causes telomere over-elongation. hTERT-immortalized AGS fibroblasts display also high fragility of chromosome ends, a marker of telomere replication stress. These results not only demonstrate the functional importance of dGTP cellular level but also reveal the critical role played by SAMHD1 in restraining telomerase processivity and safeguarding telomere stability.

RevDate: 2023-03-27
CmpDate: 2023-03-22

Liu S, Nong W, Ji L, et al (2023)

The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases.

Experimental gerontology, 174:112132.

Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.

RevDate: 2023-02-27

Levy MA, Tian J, Gandelman M, et al (2023)

A Multivitamin Mixture Protects against Oxidative Stress-Mediated Telomere Shortening.

Journal of dietary supplements [Epub ahead of print].

Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. Telomeres shorten with each cell division; hence telomere length is associated with aging and longevity. Numerous lifestyle factors have been identified that impact the rate of telomere shortening; high vitamin consumption has been associated with longer telomere length, whereas oxidative stress is associated with telomere shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins and a blend of polyphenolic compounds, could reduce telomere shortening consequent to an oxidative stress (10 uM H2O2 for 8 weeks) in a primary fibroblast cell culture model. Under conditions of oxidative stress, the median and 20[th] percentile telomere length were significantly greater (p < 0.05), and the percentage of critically short telomeres (<3000 bp) was significantly less (p < 0.05) in cells treated with the multivitamin mixture at 4, 15 and 60 ug/ml compared to control (0 ug/ml). Median and 20[th] percentile telomere shortening rate was also reduced under the same conditions (p < 0.05). Taken together, these findings demonstrate that the multivitamin mixture protects against oxidative stress-mediated telomere shortening in cell culture, findings which may have implications in human health.

RevDate: 2023-05-23
CmpDate: 2023-05-23

Pepke ML, Ringsby TH, DTA Eisenberg (2023)

The evolution of early-life telomere length, pace-of-life and telomere-chromosome length dynamics in birds.

Molecular ecology, 32(11):2898-2912.

Telomeres, the short DNA sequences that protect chromosome ends, are an ancient molecular structure, which is highly conserved across most eukaryotes. Species differ in their telomere lengths, but the causes of this variation are not well understood. Here, we demonstrate that mean early-life telomere length is an evolutionary labile trait across 57 bird species (representing 35 families in 12 orders) with the greatest trait diversity found among passerines. Among these species, telomeres are significantly shorter in fast-lived than in slow-lived species, suggesting that telomere length may have evolved to mediate trade-offs between physiological requirements underlying the diversity of pace-of-life strategies in birds. This association was attenuated when excluding studies that may include interstitial telomeres in the estimation of mean telomere length. Curiously, within some species, larger individual chromosome size predicts longer telomere lengths on that chromosome, leading to the hypothesis that telomere length also covaries with chromosome length across species. We show that longer mean chromosome length or genome size tends to be associated with longer mean early-life telomere length (measured across all chromosomes) within a phylogenetic framework constituting up to 31 bird species. These associations were strengthened when excluding highly influential outliers. However, sensitivity analyses suggested that they were susceptible to sample size effects and not robust to the exclusion of studies that may include interstitial telomeres. Combined, our analyses generalize patterns previously found within a few species and provide potential adaptive explanations for the 10-fold variation in telomere lengths observed among birds.

RevDate: 2023-02-28

Zhang X, Zhang C, Zhou D, et al (2023)

Telomeres cooperate in zygotic genome activation by affecting DUX4/Dux transcription.

iScience, 26(3):106158.

Zygotic genome activation (ZGA) is initiated once the genome chromatin state is organized in the newly formed zygote. Telomeres are specialized chromatin structures at the ends of chromosomes and are reset during early embryogenesis, while the details and significance of telomere changes in preimplantation embryos remain unclear. We demonstrated that the telomere length was shortened in the minor ZGA stage and significantly elongated in the major ZGA stage of human and mouse embryos. Expression of the ZGA pioneer factor DUX4/Dux was negatively correlated with the telomere length. ATAC sequencing data revealed that the chromatin accessibility peaks on the DUX4 promoter region (i.e., the subtelomere of chromosome 4q) were transiently augmented in human minor ZGA. Reduction of telomeric heterochromatin H3K9me3 in the telomeric region also synergistically activated DUX4 expression with p53 in human embryonic stem cells. We propose herein that telomeres regulate the expression of DUX4/Dux through chromatin remodeling and are thereby involved in ZGA.

RevDate: 2023-08-11

Lin Y, Ye C, Li X, et al (2023)

quarTeT: a telomere-to-telomere toolkit for gap-free genome assembly and centromeric repeat identification.

Horticulture research, 10(8):uhad127.

A high-quality genome is the basis for studies on functional, evolutionary, and comparative genomics. The majority of attention has been paid to the solution of complex chromosome structures and highly repetitive sequences, along with the emergence of a new 'telomere-to-telomere (T2T) assembly' era. However, the bioinformatic tools for the automatic construction and/or characterization of T2T genome are limited. Here, we developed a user-friendly web toolkit, quarTeT, which currently includes four modules: AssemblyMapper, GapFiller, TeloExplorer, and CentroMiner. First, AssemblyMapper is designed to assemble phased contigs into the chromosome-level genome by referring to a closely related genome. Then, GapFiller would endeavor to fill all unclosed gaps in a given genome with the aid of additional ultra-long sequences. Finally, TeloExplorer and CentroMiner are applied to identify candidate telomere and centromere as well as their localizations on each chromosome. These four modules can be used alone or in combination with each other for T2T genome assembly and characterization. As a case study, by adopting the entire modular functions of quarTeT, we have achieved the Actinidia chinensis genome assembly that is of a quality comparable to the reported genome Hongyang v4.0, which was assembled with the addition of manual handling. Further evaluation of CentroMiner by searching centromeres in Arabidopsis thaliana and Oryza sativa genomes showed that quarTeT is capable of identifying all the centromeric regions that have been previously detected by experimental methods. Collectively, quarTeT is an efficient toolkit for studies of large-scale T2T genomes and can be accessed at without registration.

RevDate: 2023-08-07

Tang L, Li D, Wang J, et al (2023)

Ambient air pollution, genetic risk and telomere length in UK biobank.

Journal of exposure science & environmental epidemiology [Epub ahead of print].

BACKGROUND: Telomere length (TL) is a biomarker of genomic aging. The evidence on the association between TL and air pollution was inconsistent. Besides, the modification effect of genetic susceptibility on the air pollution-TL association remains unknown.

OBJECTIVE: We aimed to evaluate the association of ambient air pollution with TL and further assess the modification effect of genetic susceptibility.

METHODS: 433,535 participants with complete data of TL and air pollutants in UK Biobank were included. Annual average exposure of NO2, NOx, PM10 and PM2.5 was estimated by applying land use regression models. Genetic risk score (GRS) was constructed using reported telomere-related SNPs. Leukocyte TL was measured by quantitative polymerase chain reaction (qPCR). Multivariable linear regression models were employed to conduct associational analyses.

RESULTS: Categorical exposure models and RCS models both indicated U-shaped (for NO2 and NOx) and L-shaped (for PM10 and PM2.5) correlations between air pollution and TL. In comparison to the lowest quartile, the 2nd and 3rd quartile of NO2 (q2: -1.3% [-2.1%, -0.4%]; q3: -1.2% [-2.0%, -0.3%], NOx (q2: -1.3% [-2.1%, -0.5%]; q3: -1.4% [-2.2%, -0.5%]), PM2.5 (q2: -0.8% [-1.7%, 0.0%]; q3: -1.3% [-2.2%, -0.5%]), and the third quartile of PM10 (q3: -1.1% [-1.9%, -0.2%]) were inversely associated with TL. The highest quartile of NO2 was positively correlated with TL (q4: 1.0% [0.0%, 2.0%]), whereas the negative correlation between the highest quartile of other pollutants and TL was also attenuated and no longer significant. In the genetic analyses, synergistic interactions were observed between the 4th quartile of three air pollutants (NO2, NOx, and PM2.5) and genetic risk.

IMPACT STATEMENT: Our study for the first time revealed a non-linear trend for the association between air pollution and telomere length. The genetic analyses suggested synergistic interactions between air pollution and genetic risk on the air pollution-TL association. These findings may shed new light on air pollution's health effects, offer suggestions for identifying at-risk individuals, and provide hints regarding further investigation into gene-environment interactions.

RevDate: 2023-08-07

Ojeda-Rodriguez A, Alcala-Diaz JF, Rangel-Zuñiga OA, et al (2023)

Association between telomere length and intima-media thickness of both common carotid arteries in patients with coronary heart disease: From the CORDIOPREV randomized controlled trial.

Atherosclerosis, 380:117193 pii:S0021-9150(23)05100-6 [Epub ahead of print].

BACKGROUND AND AIMS: A critical telomere length (TL) is associated with cardiovascular mortality. Dietary habits have been demonstrated to affect cardiovascular risk. However, it remains unclear how exactly TL determines the response to specific dietary approaches in the reduction of arterial injury. We aimed to evaluate whether TL was associated with the progression of arterial injury (assessed by intima-media thickness of both common carotid arteries: IMT-CC), after long-term consumption of two healthy dietary models in patients with coronary heart disease (CHD).

METHODS: From the 1002 CHD patients of the CORDIOPREV study, 903 completed IMT-CC and TL evaluation at baseline and were randomized to follow a Mediterranean diet or a low-fat diet for 5 years.

RESULTS: Patients at risk of short TL (TL < 20th percentile) presented an elevated IMT-CC, (0.79 ± 0.17 vs patients at non-risk 0.74 ± 0.17 p < 0.001). TL and IMT-CC showed an inverse association (β = -0.035, p = 0.002). Patients who consumed a Mediterranean diet, regardless of the risk of short TL, showed a significant decrease in IMT-CC, with a higher reduction in those patients with risk of short TL (-0.03 ± 0.11, p = 0.036). TL (β = 0.019, p = 0.024), age (β = -0.001, p = 0.031), energy intake (β = -0.000, p = 0.036), use of statins (β = -0.027, p = 0.028) and allocation into the Mediterranean diet (vs low-fat diet) (β = -0.024, p = 0.003) were significant contributors to changes in IMT-CC.

CONCLUSIONS: Patients who had a reduced TL exhibited a greater decrease in IMT-CC after consuming a Mediterranean diet.

RevDate: 2023-08-07

Kordowitzki P, Graczyk S, Mechsner S, et al (2023)

Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer.

Aging and disease pii:AD.2023.0716 [Epub ahead of print].

Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal ageindependent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.

RevDate: 2023-08-07

Tahara T, Shijimaya T, Yamazaki J, et al (2023)

Telomere shortening of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

Cancer investigation [Epub ahead of print].

Telomere shortening is deeply involved in many types of cancer. Telomere length of esophageal adenocarcinoma (EAC) and Barrett's esophagus (BE) was examined in Japanese patients. Among BE from cancer free patients (Cancer free), BE from patients with EAC (Adjacent) and EAC tissue (Cancer), Cancer free group presented the longest telomeres, while Cancer group presented the shortest telomeres and Adjacent group presented intermediate telomeres. Direction of endoscopic biopsy, 2 o'clock direction was also significantly associated with shorter telomere length in non-neoplastic BE (P = 0.027). Shortened telomere highlighted the impact of this molecular change in early carcinogenesis in EAC.

RevDate: 2023-08-06

Xiang M, Pilling LC, Melzer D, et al (2023)

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

GeroScience [Epub ahead of print].

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days (n = 54,180). Relative mean LTL at baseline (5-6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).

RevDate: 2023-08-06

Snyder ME, Anderson MR, Benvenuto LJ, et al (2023)

Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis.

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation pii:S1053-2498(23)01960-5 [Epub ahead of print].

PURPOSE: Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere length (ST). Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs.

METHODS: We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres, 49 with long telomers) as well as a subset from both cohorts who had cryopreserved PBMC at least one timepoint, 6 months post-transplantation. Circulating T cells from before transplantation and at 6 and 12 months-post transplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) acute cellular rejection.

RESULTS: IPF-LTRs with ST were found to have premature 'aging' of their circulating T cell compartment, with age-agnostic elevations in post-transplant terminal differentiation of CD8[+] T cells, increased granzyme B positivity of both CD8[+] and CD4[+] T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort.

CONCLUSION: IPF-LTRs with ST have premature 'aging' of their circulating T cell compartment post transplantation, and a clear age-related decline in ACR burden.

RevDate: 2023-08-07
CmpDate: 2023-08-07

Zou J, Chu S, Bao Q, et al (2023)

Telomere maintenance genes-derived prognosis signature characterizes immune landscape and predicts prognosis of head and neck squamous cell carcinoma.

Medicine, 102(31):e34586.

Telomere dysfunction has been identified as a biological marker of cancer progression in several types of cancer, including Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to characterize the telomere maintenance genes (TMG)-related signature in prognosis and treatment response in HNSCC. The transcriptome and clinical data of HNSCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, respectively. Non-negative matrix factorization (NMF) was used to identify molecular subtypes derived from TMG. Gene set enrichment analysis (GSEA) was performed to analyze the differentially expressed pathways between subtypes, and a risk score model derived from TMG was established. Kaplan-Meier survival analysis was used to evaluate inter-group prognostic features, and the correlation between TMG-derived molecular subtypes and risk score model with immune infiltration, immunotherapy, and chemosensitivity was assessed. Two HNSCC subtypes were identified based on 59 TMG-related genes, which exhibit significant heterogeneity in prognosis, immune cell infiltration, and treatment response. Additionally, a TMG-derived risk signature containing 9 genes was developed to assess the prognosis of HNSCC patients. The signature had significant predictive ability for HNSCC prognosis and was significantly correlated with immune cell infiltration and immunotherapy response. A nomogram integrating the risk signature, N stage and radiotherapy was constructed to predict 1-, 3-, and 5-year overall survival (OS) of HNSCC patients, which had better performance than other prognostic models and included TMG-derived risk score, radiotherapy, and N stage. This study identified TMG-derived molecular subtypes in HNSCC and developed a novel prognostic score model, highlighting the potential value of TMG in HNSCC prognosis and immunotherapy.

RevDate: 2023-08-05

Jiang T, Mo X, Zhan R, et al (2023)

Causal pathway from telomere length to occurrence and 28-day mortality of sepsis: an observational and mendelian randomization study.

Aging, 15: pii:204937 [Epub ahead of print].

BACKGROUND: Telomeres are considered to be a physiological marker of aging. Elucidating relationship between telomere length and sepsis is an essential step towards understanding the biological processes involved in sepsis and its salvation. Mendelian randomization studies based on SNPs have given us new insights into genetic susceptibility to disease.

OBJECTIVES: To explore the causal pathway from telomere length to occurrence and 28-day mobility of sepsis.

METHODS: Leveraging genetic information resource of UK Biobank, we captured three groups of large-scale GWAS data: leukocyte telomere length (LTL), sepsis and all-cause death of 28-day. Study design consisted of three parts: forward analysis, reverse analysis and one-way analysis. Genetic instrumental variables were selected for different analyses under the premise that three MR core assumptions were satisfied. Causality was determined by means of IVW.

RESULTS: In forward analysis, we did not observe a significant causal pathway from sepsis to LTL under IVW model: β (SE) was -0.0051 (0.0075) with a p-value of 0.499. In reverse analysis, based on the IVW model, the OR (95% CI) was 0.89 (0.80-0.99) and the p-values was 0.043; based on the results of leave out method and single SNP analysis, we obtained seven key SNPs. There were results of IVW model in the one-way analysis: β (SE) was -0.0287(0.1261).

CONCLUSIONS: Short LTL increases susceptibility to sepsis, but sepsis does not shorten telomere length. LTL does not affect sepsis 28-day all-cause mortality and does not serve as a causal intermediate in gene regulation during the progression of sepsis to 28-day death.

RevDate: 2023-08-03

Lombardi F, Sanfilippo A, Fabbiani M, et al (2023)

Blood telomere length gain in people living with HIV switching to dolutegravir plus lamivudine versus continuing triple regimen: a longitudinal, prospective, matched, controlled study.

The Journal of antimicrobial chemotherapy pii:7236277 [Epub ahead of print].

BACKGROUND: Blood telomere length (BTL) is a validated biomarker of aging. ART reduces immunosenescence and has benefits in terms of BTL in people living with HIV (PLWH). However, it has also been observed that ART containing NRTIs, such as tenofovir or abacavir, which are potent inhibitors of human telomerase activity in vitro, might negatively affect BTL. Here we investigated the effects on BTL 1 year after switching to a dual therapy (DT) with dolutegravir + lamivudine versus maintaining a standard triple therapy (TT) with a two-NRTI backbone and an anchor drug.

METHODS: This was a longitudinal, prospective, matched, controlled study that included virologically suppressed adults on stable three-drug ART who either switched at baseline (BL) to DT or maintained TT. The DT and TT groups were 1:1 matched for age, sex, years since HIV diagnosis, years on ART and anchor drug. BTL was assessed by a monochrome multiplex qPCR at BL and after 48 weeks (W48).

RESULTS: We enrolled 120 PLWH, i.e. 60 participants in each group. At BL, the BTL means were comparable between the two groups (P = 0.973). At W48, viro-immunological status was stable and an overall increase in the mean BTL was observed, i.e., +0.161 (95%CI, 0.054-0.268) (P = 0.004). However, the within-group analysis showed a significant mean BTL gain in the DT group (P = 0.003) but not in the TT group (P = 0.656).

CONCLUSIONS: In this setting of virologically suppressed PLWH, simplifying to dolutegravir + lamivudine was associated with a higher gain in BTL than maintaining triple therapy after the 1 year follow-up. These findings suggest that as a simplification strategy dolutegravir + lamivudine might have a positive effect on BTL.

RevDate: 2023-08-03

Naspolini NF, Sichieri R, Barbosa Cunha D, et al (2023)

Dietary patterns, obesity markers and leukocyte telomere length among Brazilian civil servants: cross-sectional results from the Pro-Saude study - CORRIGENDUM.

Public health nutrition pii:S1368980023001477 [Epub ahead of print].

RevDate: 2023-08-02

Hourvitz N, Awad A, Y Tzfati (2023)

The many faces of the helicase RTEL1 at telomeres and beyond.

Trends in cell biology pii:S0962-8924(23)00135-6 [Epub ahead of print].

Regulator of telomere elongation 1 (RTEL1) is known as a DNA helicase that is important for telomeres and genome integrity. However, the diverse phenotypes of RTEL1 dysfunction, the wide spectrum of symptoms caused by germline RTEL1 mutations, and the association of RTEL1 mutations with cancers suggest that RTEL1 is a complex machine that interacts with DNA, RNA, and proteins, and functions in diverse cellular pathways. We summarize the proposed functions of RTEL1 and discuss their implications for telomere maintenance. Studying RTEL1 is crucial for understanding the complex interplay between telomere maintenance and other nuclear pathways, and how compromising these pathways causes telomere biology diseases, various aging-associated pathologies, and cancer.

RevDate: 2023-08-02

Sullivan SM, Cole B, Lane J, et al (2023)

Predicted leukocyte telomere length and risk of myeloid neoplasms.

Human molecular genetics pii:7235667 [Epub ahead of print].

Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per~1200 base pair [bp] increase in LTL, 95% CI:1.65, 9.85 using Codd et al. [2013], OR = 3.48 per one-standard deviation increase in LTL, 95% CI:1.74, 6.97 using Li et al. [2020], and OR = 2.59 per 1000 bp increase in LTL, 95% CI:1.03, 6.52 using Taub et al. [2022] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.

RevDate: 2023-08-03
CmpDate: 2023-08-03

Singh P, Gazy I, M Kupiec (2023)

Control of telomere length in yeast by SUMOylated PCNA and the Elg1 PCNA unloader.

eLife, 12:.

Telomeres cap and protect the linear eukaryotic chromosomes. Telomere length is determined by an equilibrium between positive and negative regulators of telomerase activity. A systematic screen for yeast mutants that affect telomere length maintenance in the yeast Saccharomyces cerevisiae revealed that mutations in any of ~500 genes affects telomere length. One of the genes that, when mutated, causes telomere elongation is ELG1, which encodes an unloader of PCNA, the processivity factor for replicative DNA polymerases. PCNA can undergo SUMOylation on two conserved residues, K164 and K127, or ubiquitination at lysine 164. These modifications have already been implicated in genome stability processes. We report that SUMOylated PCNA acts as a signal that positively regulates telomerase activity. We also uncovered physical interactions between Elg1 and the CST (Cdc13-Stn1-Ten) complex and addressed the mechanism by which Elg1 and Stn1 negatively regulates telomere elongation, coordinated by SUMO. We discuss these results with respect to how chromosomal replication and telomere elongation are coordinated.

RevDate: 2023-08-01

Sebastiano M, Jouanneau W, Blévin P, et al (2023)

Physiological effects of PFAS exposure in seabird chicks: A multi-species study of thyroid hormone triiodothyronine, body condition and telomere length in South Western France.

The Science of the total environment pii:S0048-9697(23)04545-X [Epub ahead of print].

There is growing evidence that poly and perfluoroalkyl substances (PFAS) exposure leads to the disruption of thyroid hormones including thyroxine (T4) and triiodothyronine (T3), and may affect telomeres, repetitive nucleotide sequences which protects chromosome ends. Many seabird species are long-lived top predators thus exhibit high contaminant levels, and PFAS-disrupting effects on physiology have been documented especially in relation to the endocrine system in adults. On the contrary, studies on the developmental period (i.e., chicks), during which exposure to environmental contaminants may have a greater impact on physiological traits, remain scarce to this date. We carried out a multi-species study with the aim to assess whether and to which extent chicks of four gull species (herring gull, great and lesser black-backed gull, yellow-legged gull) in South Western France are contaminated by PFAS, and to bring further evidence about their potential physiological consequences. Linear PFOS showed concentrations of concern as it was generally >10 times higher than the other PFAS, and exceeded a threshold toxicity level (calculated from previous studies in birds) in almost all sampled chicks. Nonetheless, in herring gull male chicks, total T3 levels were significantly and negatively associated with perfluorodecanoate (PFDA) and perfluorododecanoate (PFDoDA) and positively associated with perfluorotetradecanoate (PFTeDA) in female chicks. Total T3 levels were also positively associated with PFDoDA in great black backed gull male chicks and with perfluorotridecanoate (PFTrDA) in lesser black backed gull chicks. In lesser and great black-backed gulls, both females and males showed significant negative associations between several PFAS and their body condition, and a positive association between telomere length and L-PFOS in the yellow-legged gull. These results corroborate previous findings and need to be further explored as they suggest that PFAS may interfere with the physiological status of chicks during the developmental period, potentially inducing long-lasting consequences.

RevDate: 2023-08-01

Zhao P, Deng B, Kang Q, et al (2023)

Recipients with acute myeloid leukemia with a long telomere and donors with a short telomere have a higher relapse rate within 1-year post-transplantation.

Minerva medica pii:S0026-4806.23.08742-6 [Epub ahead of print].

RevDate: 2023-08-01

Guo M, Songyang Z, Y Xiong (2023)

ChArmTelo Enables Large-Scale Chromosome Arm-Level Telomere Analysis across Human Populations and in Cancer Patients.

Small methods [Epub ahead of print].

Telomeres are structures protecting chromosome ends. However, a scalable and cost-effective method to investigate chromosome arm-level (ChArm) telomeres (Telos) in large-scale projects is still lacking, hindering intensive investigation of high-resolution telomeres across cancers and other diseases. Here, ChArmTelo, the first computational toolbox to analyze telomeres at chromosome arm level in human and other animal species, using 10X linked-read and similar technologies, is presented. ChArmTelo currently consists of two algorithms, TeloEM and TeloKnow, for arm-level telomere length (TL) analysis. The algorithms are demonstrated by comprehensive analysis of chromosome arm-level telomere lengths (chArmTLs) in nearly 400 whole genome sequencing samples (WGS) from human populations and animals, including healthy and cancer samples. Notably, considerable performance improvement contributed by using the latest complete telomere-to-telomere reference genome (CHM13v2), compared to hg38, is shown. ChArmTelo reveals population-specific chArmTL differences and liver cancer signatures of chArmTLs and that DNA replication origin disruption may contribute to cancer by affecting TLs. Importantly, ChArmTelo can be readily applied to tens of thousands of cancer and healthy samples with published WGS data.

RevDate: 2023-07-31

O'Donnell S, Yue JX, Saada OA, et al (2023)

Telomere-to-telomere assemblies of 142 strains characterize the genome structural landscape in Saccharomyces cerevisiae.

Nature genetics [Epub ahead of print].

Pangenomes provide access to an accurate representation of the genetic diversity of species, both in terms of sequence polymorphisms and structural variants (SVs). Here we generated the Saccharomyces cerevisiae Reference Assembly Panel (ScRAP) comprising reference-quality genomes for 142 strains representing the species' phylogenetic and ecological diversity. The ScRAP includes phased haplotype assemblies for several heterozygous diploid and polyploid isolates. We identified circa (ca.) 4,800 nonredundant SVs that provide a broad view of the genomic diversity, including the dynamics of telomere length and transposable elements. We uncovered frequent cases of complex aneuploidies where large chromosomes underwent large deletions and translocations. We found that SVs can impact gene expression near the breakpoints and substantially contribute to gene repertoire evolution. We also discovered that horizontally acquired regions insert at chromosome ends and can generate new telomeres. Overall, the ScRAP demonstrates the benefit of a pangenome in understanding genome evolution at population scale.

RevDate: 2023-08-01

Dasanayaka NN, Sirisena ND, N Samaranayake (2023)

Associations of meditation with telomere dynamics: a case-control study in healthy adults.

Frontiers in psychology, 14:1222863.

INTRODUCTION: Telomeres are protective end caps of chromosomes which naturally shorten with each cell division and thus with age. Short telomeres have been associated with many age-related diseases. Meditation has come to the fore as a mind-body practice which could influence the telomere dynamics underlying these phenomena. We previously reported meditation to be associated with higher telomerase levels, mindfulness and quality of life. Here, reporting on the same study population, we describe associations between long-term meditation and telomere length (TL), expression of hTERT and hTR genes and methylation of the promoter region of hTERT gene.

METHODS: Thirty healthy meditators and matched non-meditators were recruited. TL was measured using quantitative PCR, gene expression was assessed using reverse transcriptase PCR, and methylation level was quantified by bisulfite-specific PCR followed by Sanger sequencing. Comparisons between meditators and controls were carried out using t-tests, while Pearson correlation was used to identify correlations, and regression was used to identify predictors.

RESULTS: Males comprised 63.4% of each group with an average age of 43 years. On average, they had meditated daily for 5.82 h (±3.45) for 6.8 years (±3.27). Meditators had longer relative TLs (p = 0.020), and TL decreased with age (p < 0.001) but was not associated with other socio-demographic variables. Regression analysis showed that age (p < 0.001) and duration of meditation (p = 0.003) significantly predicted TL. The meditators showed higher relative expression of hTERT (p = 0.020) and hTR (p = 0.029) genes while the methylation level of the promoter region of hTERT gene was significantly lower when compared to non-meditators (p < 0.001). Negative correlations were identified between the methylation level of the promoter region of hTERT gene and the expression of the hTERT gene (p = 0.001) and duration of meditation (p = 0.001).

CONCLUSION: The findings suggest that meditation as a lifestyle practice has multi-level beneficial effects on telomere dynamics with potential to promote healthy aging.

RevDate: 2023-08-01

Ratanatharathorn A, Roberts AL, Chibnik LB, et al (2023)

Posttraumatic Stress Disorder, Depression, and Accelerated Aging: Leukocyte Telomere Length in the Nurses' Health Study II.

Biological psychiatry global open science, 3(3):510-518.

BACKGROUND: Exposure to trauma, posttraumatic stress disorder (PTSD), and depression have been independently associated with leukocyte telomere length (LTL), a cellular marker of aging associated with mortality and age-related diseases. However, the joint contributions of trauma and its psychological sequelae on LTL have not been examined.

METHODS: We conducted an analysis of LTL in a subset of women from the Nurses' Health Study II (N = 1868). Lifetime exposure to traumatic events, PTSD, and depression was assessed with validated measures. DNA was extracted from peripheral blood leukocytes and telomere repeat copy number to single gene copy number was determined by quantitative real-time polymerase chain reaction telomere assay. Linear regression models assessed the association of trauma, PTSD, and depression with LTL after adjustment for health behaviors and medical conditions.

RESULTS: Trauma, PTSD, and depression were not independently associated with LTL in mutually adjusted models. However, individuals with severe psychological distress-characterized by comorbid PTSD and depression-had shorter LTL equivalent to being 7.62 years older (95% CI, 0.02 to 17.97) than participants who had never experienced a traumatic event and were not depressed. Further examination found only an association among individuals with the highest number of PTSD symptoms and comorbid depression equivalent to 9.71 additional years of aging (95% CI, 1.36 to 20.49). No effect was found among individuals meeting the minimum threshold for probable PTSD with comorbid depression.

CONCLUSIONS: Severe psychological distress, as indicated by the presence of comorbid PTSD and depression, may be associated with shorter LTL.

RevDate: 2023-07-29

Cai Y, Guo H, Zhou J, et al (2023)

An alternative extension of telomeres related prognostic model to predict survival in lower grade glioma.

Journal of cancer research and clinical oncology [Epub ahead of print].

OBJECTIVE: The alternative extension of the telomeres (ALT) mechanism is activated in lower grade glioma (LGG), but the role of the ALT mechanism has not been well discussed. The primary purpose was to demonstrate the significance of the ALT mechanism in prognosis estimation for LGG patients.

METHOD: Gene expression and clinical data of LGG patients were collected from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohort, respectively. ALT-related genes obtained from the TelNet database and potential prognostic genes related to ALT were selected by LASSO regression to calculate an ALT-related risk score. Multivariate Cox regression analysis was performed to construct a prognosis signature, and a nomogram was used to represent this signature. Possible pathways of the ALT-related risk score are explored by enrichment analysis.

RESULT: The ALT-related risk score was calculated based on the LASSO regression coefficients of 22 genes and then divided into high-risk and low-risk groups according to the median. The ALT-related risk score is an independent predictor of LGG (HR and 95% CI in CGGA cohort: 5.70 (3.79, 8.58); in TCGA cohort: 1.96 (1.09, 3.54)). ROC analysis indicated that the model contained ALT-related risk score was superior to conventional clinical features (AUC: 0.818 vs 0.729) in CGGA cohorts. The results in the TCGA cohort also shown a powerful ability of ALT-related risk score (AUC: 0.766 vs 0.691). The predicted probability and actual probability of the nomogram are consistent. Enrichment analysis demonstrated that the ALT mechanism was involved in the cell cycle, DNA repair, immune processes, and others.

CONCLUSION: ALT-related risk score based on the 22-gene is an important factor in predicting the prognosis of LGG patients.

RevDate: 2023-07-31
CmpDate: 2023-07-31

Dmitrenko OP, Abramova OI, Karpova NS, et al (2023)

Relative Telomere Length Is Associated with the Risk of Development and Severity of the Course of Age-Related Macular Degeneration in the Russian Population.

International journal of molecular sciences, 24(14):.

One of the most significant factors for age-related macular degeneration (AMD) development is considered to be aging, the processes of which are closely associated with telomere shortening. The different forms, indicators of aggressiveness, and intensities of AMD can be observed in the same age group, confirming the need to find a biomarker for early diagnosis and be capable of monitoring the progression of the pathological process. Therefore, we investigated whether the relative telomere length (RTL) has any connection with the risk of development of disease and its progression. RTL was measured using RT-PCR in 166 people, including 96 patients with AMD. RTL was significantly lower in patients with AMD. Women were more likely to develop AMD than men (odds ratio (OR) = 9.53 × 10[6] vs. OR = 1.04 × 10[8], respectively). The decrease in RTL in patients reliably correlated with the progression of AMD, and the smallest RTL was observed in late-stage patients. RTL < 0.8 is a significant risk factor for disease progression. The results of our research showed that RTL may be considered as a potential biomarker and a promising predictor of disease progression in patients with early AMD.

RevDate: 2023-07-31

O'Daniel SE, Kochan KJ, Long CR, et al (2023)

Comparison of Telomere Length in Age-Matched Primiparous and Multiparous Brahman Cows.

Animals : an open access journal from MDPI, 13(14):.

Physiological and psychological stressors have been associated with the attrition of telomeres, which are the protective caps of chromosomes. This study compares the telomere length (TL) in 4-year-old Brahman cows grouped by the first parity (n = 8) and the second parity (n = 11). The cows were bled via jugular venipuncture, weighed, and had their body condition scores recorded at Day -28 prior to calving and at Day + 7 and Day + 28 post-calving. The duration of labor (Dlabor) and parturition ease were recorded. The peripheral leukocytes were isolated, the leukocyte blood count with differential was recorded, and the genomic DNA was extracted. The relative quantity of telomere products, which is proportional to the average TL, was determined via multiplex quantitative PCR using the ratio (T/S ratio) of bovine telomere and β-globulin DNA. Standards of the bovine telomere (10[12]-10[7] dilution series) and β-globulin (10[9]-10[4] dilution series) genes were utilized to produce relative copy numbers. The samples were assayed in triplicate and were included if the triplicate Cq difference was less than 0.25 cycles. The parity was the fixed effect, and the random effects included the sire and day repeated with the cow as the subject. Statistical significance was not observed in the leukocyte number or type (p > 0.1). A reduction in the TL of approximately 9225 telomeric copies was found between Parity 1 and Parity 2 (p = 0.02). A trend was found between the TL and Dlabor (p = 0.06). The stress of parturition and raising the first calf of a cow's life may be responsible for TL attenuation. Parity may be considered a stressor of cow longevity.

RevDate: 2023-07-28

Bazan N, Bhattacharjee S, Kala-Bhattacharjee S, et al (2023)

Elovanoids are neural resiliency epigenomic regulators targeting histone modifications, DNA methylation, tau phosphorylation, telomere integrity, senescence programming, and dendrite integrity.

Research square

Cellular identity, developmental reorganization, genomic structure modulation, and susceptibility to diseases are determined by epigenomic regulation by multiple signaling interplay. Here we demonstrate that elovanoids (ELVs), mediators derived from very-long-chain polyunsaturated fatty acids (VLC-PUFAs, n-3, C > 28), and their precursors in neurons in culture overcome the damage triggered by oligomeric amyloid-beta (OAβ), erastin (ferroptosis-dependent cell death), or other insults that target epigenomic signaling. We uncover that ELVs counteract damage targeting histones H3K9 and H3K27 methylation and acetylation; tau hyperphosphorylation (pThr181, pThr217, pThr231, and pSer202/pThr205 (AT8)); senescence gene programming (p16INK4a, p27KIP, p21CIP1, and p53); DNA methylation (DNAm) modifying enzymes: TET (DNA hydroxymethylase), DNA methyltransferase, DNA demethylase, and DNAm (5mC) phenotype. Moreover, ELVs revert OAβ-triggered telomere length (TL) attrition as well as upregulation of telomerase reverse transcriptase (TERT) expression fostering dendrite protection and neuronal survival. Thus, ELVs modulate epigenomic resiliency by pleiotropic interrelated signaling.

RevDate: 2023-07-26

Sung S, Kim E, Niida H, et al (2023)

Distinct characteristics of two types of alternative lengthening of telomeres in mouse embryonic stem cells.

Nucleic acids research pii:7230093 [Epub ahead of print].

Telomere length must be maintained in actively dividing cells to avoid cellular arrest or death. In the absence of telomerase activity, activation of alternative lengthening of telomeres (ALT) allows the maintenance of telomeric length and prolongs the cellular lifespan. Our previous studies have established two types of ALT survivors from mouse embryonic stem cells. The key differences between these ALT survivors are telomere-constituting sequences: non-telomeric sequences and canonical telomeric repeats, with each type of ALT survivors being referred to as type I and type II, respectively. We explored how the characteristics of the two types of ALT lines reflect their fates using multi-omics approaches. The most notable gene expression signatures of type I and type II ALT cell lines were chromatin remodelling and DNA repair, respectively. Compared with type II cells, type I ALT cells accumulated more mutations and demonstrated persistent telomere instability. These findings indicate that cells of the same origin have separate routes for survival, thus providing insights into the plasticity of crisis-suffering cells and cancers.

RevDate: 2023-07-26

Cai SW, T de Lange (2023)

CST-Polα/Primase: the second telomere maintenance machine.

Genes & development pii:gad.350479.123 [Epub ahead of print].

It has been known for decades that telomerase extends the 3' end of linear eukaryotic chromosomes and dictates the telomeric repeat sequence based on the template in its RNA. However, telomerase does not mitigate sequence loss at the 5' ends of chromosomes, which results from lagging strand DNA synthesis and nucleolytic processing. Therefore, a second enzyme is needed to keep telomeres intact: DNA polymerase α/Primase bound to Ctc1-Stn1-Ten1 (CST). CST-Polα/Primase maintains telomeres through a fill-in reaction that replenishes the lost sequences at the 5' ends. CST not only serves to maintain telomeres but also determines their length by keeping telomerase from overelongating telomeres. Here we discuss recent data on the evolution, structure, function, and recruitment of mammalian CST-Polα/Primase, highlighting the role of this complex and telomere length control in human disease.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

SUPPORT ESP: Click covers to order from Amazon
The ESP project will earn a commission.

Good Beginner's Books

Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )