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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 18 Apr 2021 at 06:42 Created: 

Telomeres

Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

Created with PubMed® Query: telomere[title] OR telomeres[title] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-04-17

Quque M, Paquet M, Zahn S, et al (2021)

Contrasting associations between nestling telomere length and pre and postnatal helpers' presence in a cooperatively breeding bird.

Oecologia [Epub ahead of print].

Studies on cooperative breeders have addressed the effects of non-breeding 'helpers' on reproduction and parental care, but the consequences for offspring physiology and long-term survival are less understood. Helpers are expected to benefit offspring, but their presence can also lead to decreased pre- or post-natal parental reproductive effort. To examine whether prenatal and postnatal helpers influence offspring condition, we conducted a whole-clutch cross-fostering experiment in sociable weavers (Philetairus socius) that altered the nestlings' social environment (presence/absence of helpers). We tested whether relative telomere length (rTL), an indicator of somatic maintenance, was influenced by prenatal and/or postnatal presence of helpers 9 and 17 days after hatching, and whether rTL predicted long-term survival. Nine days after hatching, we found an overall positive effect of postnatal helpers on rTL: for nestlings with prenatal helpers, a reduction in the number of helpers post-hatch was associated with shorter telomeres, while nestlings swapped from nests without helpers to nests with helpers had a larger rTL. However, when prenatal helpers were present, an increased number of helpers after hatching led to shorter telomeres. Nine-day old chicks with longer rTL tended to be more likely to survive over the 5 years following hatching. However, close to fledging, there was no detectable effect of the experiment on rTL and no link between rTL and survival. This experimental study of a wild cooperative breeder, therefore, presents partial support for the importance of the presence of helpers for offspring rTL and the link between early-life telomere length and long-term survival.

RevDate: 2021-04-17

Corfdir C, Pignon B, Szöke A, et al (2021)

[Accelerated telomere erosion in schizophrenia: A literature review].

L'Encephale pii:S0013-7006(21)00058-0 [Epub ahead of print].

Schizophrenia is associated with a weighted average of 14.5 years of potential life lost according to a recent meta-analysis. This is partly explained by high rates of suicide and a high prevalence of non-psychiatric comorbidity (cardiovascular diseases, diabetes, cancers…). However, all these causes could not fully explain the loss of life expectancy in people suffering from schizophrenia. Life expectancy has been strongly correlated with telomere length (TL). Telomeres are noncoding structures consisting of DNA TTAGGG tandem repeats and associated proteins located at the end of the chromosomes. Their role is to help preserve genome stability by protecting chromosomal ends from the loss of genetic material. The progressive loss of telomeric material during cell divisions has led researchers to consider telomeres as molecular clocks that measure the number of divisions left until cellular death. The fact that both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy has fueled the interest in the study of TL in schizophrenia. In this article, after a detailed review of the literature on the relationships between telomere length and schizophrenia, we discuss the different pathophysiological mechanisms which might explain this association. Based on this analysis, in the last part of the article we discuss potential research, therapeutic and prevention prospects. To date, the majority of the studies and meta-analyses found a decrease in TL in subjects with schizophrenia compared to control subjects. Conversely, all the studies exploring the TL in subjects suffering from first episode psychosis (FEP) have shown no significant difference from TL in control subjects. This suggests that excessive shortening of telomeres occurs during the course of the disease, thus it seems more probable that schizophrenia (or processes associated with it) affects TL rather than telomere erosion being a cause of the disorder. Several pathophysiological, non-mutually exclusive mechanisms have been proposed to explain the observed data. A first hypothesis to explain the acceleration of the physiological process of telomere erosion in schizophrenia is the activation of inflammation processes and oxidative stress as a consequence of schizophrenia per se. However, it seems more probable that reduced TL may be a result of cumulative exposure to chronic stress related to schizophrenia. Indeed, in healthy individuals a growing body of evidence has linked chronic stress to accelerated shortening of TL. This might explain why telomere erosion is too small to be detected in FEP patients who are younger and have a shorter duration of illness than subjects with schizophrenia. Based on these both explanations, telomere alterations may be considered as a biomarker of illness progression and might be useful for illness staging. Identifying processes associated with TL reduction might improve our understanding of the increased mortality and morbidity in schizophrenia, improve reliability of diagnosis, and hopefully suggest means for prevention and/or treatment. Treatments that prevent exposure and/or vulnerability to stressful life events that ameliorate schizophrenia may also prevent or decelerate telomere erosion. In this perspective, engaging subjects suffering from schizophrenia in a healthy diet and regular activity could be both promising strategies to protect telomere maintenance and improve health span at old age. In addition, the inflammatory process and oxidative stress involved in the physiopathology in at least a subgroup of subjects with schizophrenia could also be responsible for telomere erosion. Thus, an efficient anti-inflammatory therapeutic approach that targets these specific pathways could be of interest in this subgroup to limit telomere erosion. Mindfulness-based stress reduction (MBSR) therapies have been shown to reduce telomere erosion by increasing telomerase activity, although these psychological therapies should be used carefully in psychosis. Finally, advancing our understanding of the relationship between stress, inflammation and TL is of great interest for psychiatric research and for understanding stress effects in this population.

RevDate: 2021-04-15

Giaccherini M, Macauda A, Orciuolo E, et al (2021)

Genetically determined telomere length and multiple myeloma risk and outcome.

Blood cancer journal, 11(4):74.

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10-6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

RevDate: 2021-04-15

Vessoni AT, Zhang T, Quinet A, et al (2021)

Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.

The Journal of cell biology, 220(6):.

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.

RevDate: 2021-04-14

Hackeng WM, Brosens LAA, Kim JY, et al (2021)

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut pii:gutjnl-2020-322595 [Epub ahead of print].

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

RevDate: 2021-04-16

Cicconi A, Micheli E, Raffa GD, et al (2021)

Atomic Force Microscopy Reveals that the Drosophila Telomere-Capping Protein Verrocchio Is a Single-Stranded DNA-Binding Protein.

Methods in molecular biology (Clifton, N.J.), 2281:241-263.

Atomic force microscopy (AFM) is a scanning probe technique that allows visualization of biological samples with a nanometric resolution. Determination of the physical properties of biological molecules at a single-molecule level is achieved through topographic analysis of the sample adsorbed on a flat and smooth surface. AFM has been widely used for the structural analysis of nucleic acid-protein interactions, providing insights on binding specificity and stoichiometry of proteins forming complexes with DNA substrates. Analysis of single-stranded DNA-binding proteins by AFM requires specific single-stranded/double-stranded hybrid DNA molecules as substrates for protein binding. In this chapter we describe the protocol for AFM characterization of binding properties of Drosophila telomeric protein Ver using DNA constructs that mimic the structure of chromosome ends. We provide details on the methodology used, including the procedures for the generation of DNA substrates, the preparation of samples for AFM visualization, and the data analysis of AFM images. The presented procedure can be adapted for the structural studies of any single-stranded DNA-binding protein.

RevDate: 2021-04-16

de Oliveira Vitarelli M, MC Elias (2021)

Quantifying the Affinity of Trypanosoma cruzi RPA-1 to the Single-Stranded DNA Overhang of the Telomere Using Surface Plasmon Resonance.

Methods in molecular biology (Clifton, N.J.), 2281:217-228.

Surface plasmon resonance (SPR) biosensors provide real-time binding affinity measurements between a pair of biomolecules, characterizing its interaction dynamics. An example of Trypanosoma cruzi's RPA-1 and a single-stranded DNA telomere sequence is presented with detailed guidelines and fundamentals for SPR technology.

RevDate: 2021-04-12

Wei B, Shao Y, Liang J, et al (2021)

Maternal overweight but not paternal overweight before pregnancy is associated with shorter newborn telomere length: evidence from Guangxi Zhuang birth cohort in China.

BMC pregnancy and childbirth, 21(1):283.

BACKGROUND: Telomere length (TL) is variable at birth and is inversely associated with body mass index (BMI) in adulthood. A growing number of evidences suggested that a higher maternal pre-pregnancy BMI results in adverse offspring health outcomes, especially shorter newborn TL. However, a newborn's genetic endowment is equally derived from both parents, the association between parental pre-pregnancy BMI and newborn TL has been rarely discussed. We aimed to determine the association between parental pre-pregnancy BMI and newborn TL.

METHODS: A total of 1082 parent-newborn pairs were recruited from the Guangxi Zhuang Birth Cohort (GZBC). TL in cord blood was measured using quantitative real-time polymerase chain reaction (qPCR) and expressed as the ratio of telomere copy number to single-copy gene number (T/S). A series of linear regressions were performed to assess the associations between parental pre-pregnancy BMI and newborn TL.

RESULTS: Mothers who were overweight before pregnancy had significantly shorter cord blood telomere length in their newborns than those who were normal weight before pregnancy [percentage change: - 7.96% (95% CI: - 14.49 to - 0.69%; P = 0.032)]. Further analysis of the combined effects of parental weight status on newborn TL showed that TL was significantly shortened among newborns whose mothers were overweight and fathers were of healthy weight when compared with those whose mothers and fathers were both of normal weight [percentage change: - 8.38% (95% CI: - 15.47 to - 0.92%; P = 0.028)]. Subgroup analysis indicated these effects were more pronounced among male newborns and those whose paternal age < 31 years or maternal age ≥ 28 years at delivery.

CONCLUSIONS: Maternal pre-pregnancy overweight, but not paternal pre-pregnancy overweight is associated with shorter newborn TL. Weight control in reproductive women and effective healthy weight management before pregnancy may be of particular benefit for improving longevity and life quality of offspring.

RevDate: 2021-04-14

Cerveira de Baumont A, Hoffmann MS, Bortoluzzi A, et al (2021)

Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.

Scientific reports, 11(1):7716.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

RevDate: 2021-04-08

Lin YY, Li MH, Chang YC, et al (2021)

Dynamic DNA Shortening by Telomere-Binding Protein Cdc13.

Journal of the American Chemical Society [Epub ahead of print].

Telomeres are essential for chromosome maintenance. Cdc13 is a single-stranded telomeric DNA binding protein that caps telomeres and regulates telomerase function in yeast. Although specific binding of Cdc13 to telomeric DNA is critical for telomere protection, the detail mechanism how Cdc13-DNA complex protects telomere is unclear. Using two single-molecule methods, tethered particle motion and atomic force microscopy, we demonstrate that specific binding of Cdc13 on single-stranded telomeric DNA shortens duplex DNA into distinct states differed by ∼70-80 base pairs. DNA shortening by Cdc13 is dynamic and independent of duplex DNA sequences or length. Significantly, we found that Pif1 helicase is incapable of removing Cdc13 from the shortened DNA-Cdc13 complex, suggesting that Cdc13 forms structurally stable complex by shortening of the bound DNA. Together our data identified shortening of DNA by Cdc13 and provided an indication for efficient protection of telomere ends by the shortened DNA-Cdc13 complex.

RevDate: 2021-04-08

Pathak GA, Wendt FR, Levey DF, et al (2021)

Pleiotropic effects of telomere length loci with brain morphology, and brain tissue expression.

Human molecular genetics pii:6217475 [Epub ahead of print].

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. While telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively with brain morphology measures for 101 T1-MRI based region-of-interests (ROI) (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = 4 genes; EUR = 5 genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (p ≤ 2.47 x10-6). Integrating chromatin profiles with LTL-SNPs identified 45 genes (EUR) and 79 genes (EAS) p ≤ 9.78-7. We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1, and RTEL1/RTEL1-TNFRSF6B, show convergent evidence of pleiotropy with brain morphology, gene and methylation expression, and chromatin association. Mapping gene functions to drug-gene interactions, we identified process- 'transmission across chemical synapses' (p < 2.78x10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.

RevDate: 2021-04-09

Dewhurst SM, Yao X, Rosiene J, et al (2021)

Structural variant evolution after telomere crisis.

Nature communications, 12(1):2093.

Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.

RevDate: 2021-04-07

Suliman ME, Ansari MGA, Rayis MA, et al (2021)

Telomere length and telomere repeat-binding protein in children with sickle cell disease.

Pediatric research [Epub ahead of print].

BACKGROUND: This study aimed to assess the telomere length and plasma telomere repeat-binding factor 2 (TRF2) levels in addition to other inflammatory markers in children with sickle cell disease (SCD).

METHODS: We enrolled 106 children (90 SCD and 26 controls) aged 1-15 years from the Hematology unit of King Fahad Medical City (KFMC), Saudi Arabia. Genomic DNA extracted from blood and leukocyte TL was determined using quantitative reverse transcription PCR, whereas TRF2, C-reactive protein, interleukin-6, and DNA oxidative damage were determined by using respective commercially available assays.

RESULTS: Leukocyte TL was inversely correlated with age in the SCD patients (r = -0.24, P = 0.02) and the controls (r = -0.68, P < 0.0001). In addition, SCD patients had significantly shorter TL (7.74 ± 0.81 kb) (P = 0.003) than controls (8.28 ± 0.73 kb). In contrast, no significant difference in TL among the SCD genotypes (HbSS and HbSβ0) has been observed. A modest, positive correlation was seen between TL and reticulocyte % (r = 0.21; P = 0.06). There were no significant differences in the TL and TRF2 concentrations between subjects with HbSS and HbSβ0 genotypes.

CONCLUSIONS: Short leukocyte TL was significantly associated with SCD. An inverse association was observed between TL and hemoglobin. Hydroxyurea treatment revealed no impact on TL.

IMPACT: This study explored the TL and plasma TRF2 in Saudi children with SCD. This is the first documentation that SCD children have shorter TL than their healthy counterparts, and no association between TL and TRF2 has been observed. Hydroxyurea treatment showed no impact on TL in children with SCD. This study is the first of its kind in children with SCD. It will pave the way for another study with a larger sample size in a diverse population to scrutinize these findings better.

RevDate: 2021-04-06

Raffenberg M, Engel T, Schoepf IC, et al (2021)

Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length.

The Journal of infectious diseases pii:6211111 [Epub ahead of print].

BACKGROUND: Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI).

METHODS: We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL.

RESULTS: In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables.

DISCUSSION: In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.

RevDate: 2021-04-06

Kliewer W, JL Robins (2021)

Adverse Childhood Experiences Are Associated with Cardiometabolic Risk Indicators and Telomere Length in Low-Income African-American Adolescents.

International journal of behavioral medicine [Epub ahead of print].

BACKGROUND: Adverse childhood experiences (ACEs) have been linked to increased risk for cardiovascular disease later in life, and to shortened telomere length in children and adolescents, but few studies have examined associations between ACEs and cardiometabolic risk in adolescence or potential associations between ACEs, cardiometabolic risk indicators, and telomere length in this population. The present study examined competing models of associations between adolescent ACEs (as reported by mothers); cardiovascular, inflammatory, and metabolic indicators of health risk; and leukocyte telomere length in youth.

METHOD: Data was collected from 108 low-income African-American adolescents (42.6% male; Mage = 14.27 years, SD = 1.17) living in the southeastern USA. Waist circumference was measured during a home interview, and measures of C-reactive protein, insulin resistance, and leukocyte telomere length were obtained from blood following overnight fasting.

RESULTS: Path analysis supported a main effects model, whereby ACEs were significantly associated with shortened leukocyte telomere length, higher levels of C-reactive protein, and larger waist circumferences, controlling for maternal education and adolescent sex. Exploratory analyses examining whether cardiometabolic risk mediated associations between ACEs and telomere length, or whether telomere length mediated associations between ACEs and cardiometabolic risk, were not supported.

CONCLUSIONS: ACEs are associated with risk of future cardiometabolic disorders and shortened leukocyte telomere length. Because cytogenetic changes are potentially modifiable, interventions to decrease family ACEs or alter responses to ACEs may lessen chronic disease risk in the African-American population. Targeted interventions to improve health are discussed.

RevDate: 2021-04-07

Hoerr RE, Ngo K, KL Friedman (2021)

When the Ends Justify the Means: Regulation of Telomere Addition at Double-Strand Breaks in Yeast.

Frontiers in cell and developmental biology, 9:655377.

Telomeres, repetitive sequences located at the ends of most eukaryotic chromosomes, provide a mechanism to replenish terminal sequences lost during DNA replication, limit nucleolytic resection, and protect chromosome ends from engaging in double-strand break (DSB) repair. The ribonucleoprotein telomerase contains an RNA subunit that serves as the template for the synthesis of telomeric DNA. While telomere elongation is typically primed by a 3' overhang at existing chromosome ends, telomerase can act upon internal non-telomeric sequences. Such de novo telomere addition can be programmed (for example, during chromosome fragmentation in ciliated protozoa) or can occur spontaneously in response to a chromosome break. Telomerase action at a DSB can interfere with conservative mechanisms of DNA repair and results in loss of distal sequences but may prevent additional nucleolytic resection and/or chromosome rearrangement through formation of a functional telomere (termed "chromosome healing"). Here, we review studies of spontaneous and induced DSBs in the yeast Saccharomyces cerevisiae that shed light on mechanisms that negatively regulate de novo telomere addition, in particular how the cell prevents telomerase action at DSBs while facilitating elongation of critically short telomeres. Much of our understanding comes from the use of perfect artificial telomeric tracts to "seed" de novo telomere addition. However, endogenous sequences that are enriched in thymine and guanine nucleotides on one strand (TG-rich) but do not perfectly match the telomere consensus sequence can also stimulate unusually high frequencies of telomere formation following a DSB. These observations suggest that some internal sites may fully or partially escape mechanisms that normally negatively regulate de novo telomere addition.

RevDate: 2021-04-05

Toubiana S, Tzur-Gilat A, S Selig (2021)

Epigenetic Characteristics of Human Subtelomeres Vary in Cells Utilizing the Alternative Lengthening of Telomeres (ALT) Pathway.

Life (Basel, Switzerland), 11(4): pii:life11040278.

Most human cancers circumvent senescence by activating a telomere length maintenance mechanism, most commonly involving telomerase activation. A minority of cancers utilize the recombination-based alternative lengthening of telomeres (ALT) pathway. The exact requirements for unleashing normally repressed recombination at telomeres are yet unclear. Epigenetic modifications at telomeric regions were suggested to be pivotal for activating ALT; however, conflicting data exist regarding their exact nature and necessity. To uncover common ALT-positive epigenetic characteristics, we performed a comprehensive analysis of subtelomeric DNA methylation, histone modifications, and TERRA expression in several ALT-positive and ALT-negative cell lines. We found that subtelomeric DNA methylation does not differentiate between the ALT-positive and ALT-negative groups, and most of the analyzed subtelomeres within each group do not share common DNA methylation patterns. Additionally, similar TERRA levels were measured in the ALT-positive and ALT-negative groups, and TERRA levels varied significantly among the members of the ALT-positive group. Subtelomeric H3K4 and H3K9 trimethylation also differed significantly between samples in the ALT-positive group. Our findings do not support a common route by which epigenetic modifications activate telomeric recombination in ALT-positive cells, and thus, different therapeutic approaches will be necessary to overcome ALT-dependent cellular immortalization.

RevDate: 2021-04-13

Stock CJW, EA Renzoni (2021)

Telomeres in Interstitial Lung Disease.

Journal of clinical medicine, 10(7):.

Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs.

RevDate: 2021-04-13

Travina AO, Ilicheva NV, Mittenberg AG, et al (2021)

The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins.

International journal of molecular sciences, 22(7):.

Telomere-binding factor 2 (TRF2) is part of the shelterin protein complex found at chromosome ends. Lamin A/C interacts with TRF2 and influences telomere position. TRF2 has an intrinsically disordered region between the ordered dimerization and DNA-binding domains. This domain is referred to as the long linker region of TRF2, or udTRF2. We suggest that udTRF2 might be involved in the interaction between TRF2 and lamins. The recombinant protein corresponding to the udTRF2 region along with polyclonal antibodies against this region were used in co-immunoprecipitation with purified lamina and nuclear extracts. Co-immunoprecipitation followed by Western blots and mass spectrometry indicated that udTRF2 interacts with lamins, preferably lamins A/C. The interaction did not involve any lamin-associated proteins, was not dependent on the post-translation modification of lamins, nor did it require their higher-order assembly. Besides lamins, a number of other udTRF2-interacting proteins were identified by mass spectrometry, including several heterogeneous nuclear ribonucleoproteins (hnRNP A2/B1, hnRNPA1, hnRNP A3, hnRNP K, hnRNP L, hnRNP M), splicing factors (SFPQ, NONO, SRSF1, and others), helicases (DDX5, DHX9, and Eif4a3l1), topoisomerase I, and heat shock protein 71, amongst others. Some of the identified interactors are known to be involved in telomere biology; the roles of the others remain to be investigated. Thus, the long linker region of TRF2 (udTRF2) is a regulatory domain responsible for the association between TRF2 and lamins and is involved in interactions with other proteins.

RevDate: 2021-04-05

Gavia-García G, Rosado-Pérez J, Arista-Ugalde TL, et al (2021)

Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging.

Biology, 10(4): pii:biology10040253.

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

RevDate: 2021-04-13

Pilbauerova N, Soukup T, Suchankova Kleplova T, et al (2021)

The Effect of Cultivation Passaging on the Relative Telomere Length and Proliferation Capacity of Dental Pulp Stem Cells.

Biomolecules, 11(3):.

Telomeres are repetitive nucleoprotein DNA sequences that shorten with each cell division. The stem cells activate telomerase to compensate for the telomere loss. This study aimed to evaluate the effect of cultivation passaging on the relative telomere length and proliferation capacity of dental pulp stem cells. We used ten dental pulp stem cell (DPSC) lineages stored for 12 months using uncontrolled-rate freezing to reach the study's goal. We analyzed their proliferation rate, phenotype using flow cytometry, multipotency, and relative telomere length using a qPCR analysis. We determined the relative telomere length in the added study by performing analysis after one, two, and three weeks of cultivation with no passaging. We documented the telomere attrition with increasing passaging. The shorter the relative telomere length, the lower reached population doublings, and longer population doubling time were observed at the end of the cultivation. We observed the telomere prolongation in DPSCs cultivated for two weeks with no passaging in the added subsequent study. We concluded that excessive proliferation demands on DPSCs during in vitro cultivation result in telomere attrition. We opened the theory that the telomerase might be more efficient during cell cultivation with no passaging. This observation could help in preserving the telomere length during ex vivo DPSC expansion.

RevDate: 2021-04-08

Samiec M, M Skrzyszowska (2021)

Extranuclear Inheritance of Mitochondrial Genome and Epigenetic Reprogrammability of Chromosomal Telomeres in Somatic Cell Cloning of Mammals.

International journal of molecular sciences, 22(6):.

The effectiveness of somatic cell nuclear transfer (SCNT) in mammals seems to be still characterized by the disappointingly low rates of cloned embryos, fetuses, and progeny generated. These rates are measured in relation to the numbers of nuclear-transferred oocytes and can vary depending on the technique applied to the reconstruction of enucleated oocytes. The SCNT efficiency is also largely affected by the capability of donor nuclei to be epigenetically reprogrammed in a cytoplasm of reconstructed oocytes. The epigenetic reprogrammability of donor nuclei in SCNT-derived embryos appears to be biased, to a great extent, by the extranuclear (cytoplasmic) inheritance of mitochondrial DNA (mtDNA) fractions originating from donor cells. A high frequency of mtDNA heteroplasmy occurrence can lead to disturbances in the intergenomic crosstalk between mitochondrial and nuclear compartments during the early embryogenesis of SCNT-derived embryos. These disturbances can give rise to incorrect and incomplete epigenetic reprogramming of donor nuclei in mammalian cloned embryos. The dwindling reprogrammability of donor nuclei in the blastomeres of SCNT-derived embryos can also be impacted by impaired epigenetic rearrangements within terminal ends of donor cell-descended chromosomes (i.e., telomeres). Therefore, dysfunctions in epigenetic reprogramming of donor nuclei can contribute to the enhanced attrition of telomeres. This accelerates the processes of epigenomic aging and replicative senescence in the cells forming various tissues and organs of cloned fetuses and progeny. For all the above-mentioned reasons, the current paper aims to overview the state of the art in not only molecular mechanisms underlying intergenomic communication between nuclear and mtDNA molecules in cloned embryos but also intrinsic determinants affecting unfaithful epigenetic reprogrammability of telomeres. The latter is related to their abrasion within somatic cell-inherited chromosomes.

RevDate: 2021-04-13

Eladl A, Yamaoki Y, Hoshina S, et al (2021)

Investigation of the Interaction of Human Origin Recognition Complex Subunit 1 with G-Quadruplex DNAs of Human c-myc Promoter and Telomere Regions.

International journal of molecular sciences, 22(7):.

Origin recognition complex (ORC) binds to replication origins in eukaryotic DNAs and plays an important role in replication. Although yeast ORC is known to sequence-specifically bind to a replication origin, how human ORC recognizes a replication origin remains unknown. Previous genome-wide studies revealed that guanine (G)-rich sequences, potentially forming G-quadruplex (G4) structures, are present in most replication origins in human cells. We previously suggested that the region comprising residues 413-511 of human ORC subunit 1, hORC1413-511, binds preferentially to G-rich DNAs, which form a G4 structure in the absence of hORC1413-511. Here, we investigated the interaction of hORC1413-511 with various G-rich DNAs derived from human c-myc promoter and telomere regions. Fluorescence anisotropy revealed that hORC1413-511 binds preferentially to DNAs that have G4 structures over ones having double-stranded structures. Importantly, circular dichroism (CD) and nuclear magnetic resonance (NMR) showed that those G-rich DNAs retain the G4 structures even after binding with hORC1413-511. NMR chemical shift perturbation analyses revealed that the external G-tetrad planes of the G4 structures are the primary binding sites for hORC1413-511. The present study suggests that human ORC1 may recognize replication origins through the G4 structure.

RevDate: 2021-04-13

Sharma S, Sengupta A, S Chowdhury (2021)

Emerging Molecular Connections between NM23 Proteins, Telomeres and Telomere-Associated Factors: Implications in Cancer Metastasis and Ageing.

International journal of molecular sciences, 22(7):.

The metastasis suppressor function of NM23 proteins is widely understood. Multiple enzymatic activities of NM23 proteins have also been identified. However, relatively less known interesting aspects are being revealed from recent developments that corroborate the telomeric interactions of NM23 proteins. Telomeres are known to regulate essential physiological events such as metastasis, ageing, and cellular differentiation via inter-connected signalling pathways. Here, we review the literature on the association of NM23 proteins with telomeres or telomere-related factors, and discuss the potential implications of emerging telomeric functions of NM23 proteins. Further understanding of these aspects might be instrumental in better understanding the metastasis suppressor functions of NM23 proteins.

RevDate: 2021-04-13

Luxton JJ, McKenna MJ, Lewis AM, et al (2021)

Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning.

Journal of personalized medicine, 11(3):.

The ability to predict a cancer patient's response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.

RevDate: 2021-04-15

Arantes Dos Santos G, Viana NI, Pimenta R, et al (2021)

Hypothesis: The triad androgen receptor, zinc finger proteins and telomeres modulates the global gene expression pattern during prostate cancer progression.

Medical hypotheses, 150:110566 pii:S0306-9877(21)00084-0 [Epub ahead of print].

Currently, the biggest challenge for prostate cancer (PCa) is to understand the mechanism by which the disease acquires the castration-resistant phenotype and progresses to a fatal disease. PCa has a high genetic heterogeneity, and cannot be separated into well-defined molecular subtypes. Despite this, there is consensus about the role of the androgen receptor (AR) in all stages of the disease, including the transition to the castration-resistant phenotype. Since AR is a transcription factor, we investigated the possibility of PCa presenting a pattern of global gene expression during disease progression. By analyzing the TCGA and CCLE datasets, we were able to find a pattern of waves of genes being expressed during each stage of disease progression. This phenomenon suggests the existence of a mechanism that globally regulates gene expression, being AR, telomeres, and zinc finger proteins (ZNF), three important players. The AR modulates the telomere biology, and its transcription is regulated by ZNF. Recently, a study suggested that the telomere length might influence the expression of ZNF. Thus, we hypothesized that changes in the triad AR, telomeres, and ZNF control gene expression during the progression of PCa.

RevDate: 2021-04-15

Panjawatanan P, Charoenkwan P, Tantiworawit A, et al (2021)

Telomere shortening correlates with disease severity in hemoglobin H disease patients.

Blood cells, molecules & diseases, 89:102563 pii:S1079-9796(21)00029-2 [Epub ahead of print].

Hemoglobin H (Hb H) disease is the most significant health problem of the α-thalassemia syndromes. The Hb disease patients are categorized based on their genotype to deletional and nondeletional, with the latter genotype presents the more severe clinical symptoms. Since telomere length is an indicator of biological aging and health, we hypothesized that telomere length could reflect Hb H disease's severity. In this study, we recruited 48 deletional and 47 nondeletional Hb H disease patients, along with 109 normal controls, for telomere length assessment. The leukocyte telomere length was assessed by monochromatic multiplex real-time PCR and reported as the telomere to single-copy gene (T/S) ratio. When telomere length was adjusted for age, the analysis of covariance between the control and the two Hb H disease groups revealed no significant difference. However, the telomere shortening rate was more rapid in the nondeletional Hb H disease group than those of the control and deletional Hb H disease groups. Gender analysis found that male patients have a significantly lower T/S ratio than females in the nondeletional group but not in the control and deletional groups. In the two disease groups, the T/S ratio was not influenced by ferritin level or transfusion burden but was positively correlated with the absolute reticulocyte count.

RevDate: 2021-04-05
CmpDate: 2021-04-05

Galtseva IV, Filipenko ML, Davydova YO, et al (2021)

Comparison of polymerase chain reaction and flow cytometry for measuring telomere length of human leukocytes.

Klinicheskaia laboratornaia diagnostika, 66(3):154-159.

Telomere length can be measured by polymerase chain reaction (PCR), allowing to obtain the absolute length of telomeres (ALT) in base pair, and by flow cytometry, which can only estimate the relative telomere length. The aim of the study was to compare the results of the two methods and to develop an accurate and reliable way of converting the relative telomere length to absolute. The peripheral blood from 21 donors was analyzed. Measurement of leukocyte telomere length by flow cytometry was carried out using a commercial Telomere PNA Kit / FITC (Dako, Denmark) with two CytoFLEX flow cytometers (Beckman Coulter, China) and BD FACSCanto II (Becton Dickinson, USA), obtaining the molecular equivalent of fluorescence (MEF). To measure telomere length by real-time PCR, calibrators with a known number of telomeric repeats were prepared. Two quantitative PCRs were carried out: one for telomeric repeats, the other for determining the number of genome-equivalents of DNA, three times for each sample, which made it possible to calculate ALT. A strong direct relationship was found between the MEF obtained with BD FACSCanto II and CytoFLEX (r = 0.97). Analysis of PCR and flow cytometry results showed a significant correlation between ALT and MEF. We calculated the regression equations of ALT and MEF for CytoFLEX - y = 0.0043x (r = 0.84) and for BD FACSCanto II - y = 0.0051x (r = 0.82). Correlation analysis showed a high comparability of telomere lengths measured by two methods. The obtained regression equations allow converting the results of flow cytometry into absolute values, allowing the comparison of the results of different research groups and the use of this method in clinical trials.

RevDate: 2021-04-01

Romaine SPR, Denniff M, Codd V, et al (2021)

Telomere length is independently associated with all-cause mortality in chronic heart failure.

Heart (British Cardiac Society) pii:heartjnl-2020-318654 [Epub ahead of print].

OBJECTIVE: Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.

METHODS: We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.

RESULTS: In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10-5), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10-3). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10-3). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).

CONCLUSION: In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.

RevDate: 2021-04-02
CmpDate: 2021-04-02

Wang Y, Yang JH, CJ Zhao (2021)

[Effect of moxibustion on acupoints at "opening" time on telomere length and expression of liver cell cycle regulators in aging rats].

Zhen ci yan jiu = Acupuncture research, 46(2):117-122.

OBJECTIVE: To observe the effects of "lingguibafa" moxibustion performing at the appropriate acupoints at their "opening" time on telomere length,expressions of p53 of tumor supressor genes and retinoblastoma gene(Rb)in the liver of aging rats,so as to explore its mechanisms underlying delaying senescence.

METHODS: Forty male SD rats were randomly divi-ded into normal, model, prevention and treatment groups, with 10 rats in each group. The rat model was established by intrape-ritoneally injection of D-galactose (200 mg/kg) once a day for 42 days. The rats in the prevention group were given "lingguibafa" moxibustion during modeling, while those in the treatment group were given "lingguibafa" moxibustion after modeling. Quantitative real-time PCR was used to detect the telomere length and the mRNA expressions of p53 and Rb,ELISA was used to detect the protein contents of p53 and Rb in the liver tissues.

RESULTS: Compared with the normal group, the relative telomere length of the model group was significantly shortened (P<0.01), the mRNA expressions and protein contents of p53 and Rb were significantly increased (P<0.01). After intervention and in comparison with the model group, the relative telomere length of the prevention group and the treatments group were significantly increased (P<0.01), and the expressions of p53 and Rb mRNA and protein contents were significantly reduced (P<0.01, P<0.05). There were no significant difference between the prevention and the treatment groups in the abovementioned indexes (P>0.05).

CONCLUSION: Moxibustion on acupoints at "opening" time can inhibit the shortening of telomere length and the down-regulation of the expressions of p53 and Rb in aging rats, which may contribute to its function in delaying the process of cell senescence.

RevDate: 2021-03-31

Friesen CR, Wilson M, Rollings N, et al (2021)

Exercise training has morph-specific effects on telomere, body condition and growth dynamics in a color-polymorphic lizard.

The Journal of experimental biology pii:jeb.242164 [Epub ahead of print].

Alternative reproductive tactics (ARTs) are correlated suites of sexually selected traits that are likely to impose differential physiological costs on different individuals. While moderate activity might be beneficial, animals living in the wild often work at the margins of their resources and performance limits. Individuals using ARTs may have divergent capacities for activity. When pushed beyond their respective capacities, they may experience condition loss, oxidative stress, and molecular damage that must be repaired with limited resources. We used the Australian painted dragon lizard that exhibits color-polymorphism as a model to experimentally test the effect of exercise on body condition, growth, reactive oxygen species (ROS), and telomere dynamics-a potential marker of stress and aging and a correlate of longevity. For most males, ROS tended to be lower with greater exercise; however, males with yellow throat patches-or bibs-had higher ROS than non-bibbed males. At the highest level of exercise, bibbed males exhibited telomere loss, while non-bibbed males gained telomere length; the opposite pattern was observed in the no-exercise controls. Growth was positively related to food intake but negatively correlated with telomere length at the end of the experiment. Body condition was not related to food intake but was positively correlated with increases in telomere length. These results, along with our previous work, suggest that aggressive-territory holding-bibbed males suffer physiological costs that may reduce longevity compared to non-bibbed males with superior postcopulatory traits.

RevDate: 2021-04-01

Sosnowski DW, Kliewer W, Valrie CR, et al (2021)

The Association Between Adverse Childhood Experiences and Child Telomere Length: Examining Self-Regulation as a Behavioral Mediator.

Child development, 92(2):746-759.

Childhood adversity is linked to shortened telomere length (TL), but behavioral indicators of telomere attrition remain unclear. This study examined the association between adverse childhood experiences (ACEs) and child TL, and if ACEs were indirectly associated with TL through children's self-regulatory abilities (i.e., effortful control and self-control). Hypotheses were tested using national data from teachers, parents, and their children (N = 2,527; Mage = 9.35, SD = .36 years). More ACEs were uniquely associated with short TL, and low self-control mediated the association between more ACEs and short TL. While longitudinal studies are needed to strengthen claims of causation, this study identifies a pathway from ACEs to TL that should be explored further.

RevDate: 2021-04-02

Bliznina A, Masunaga A, Mansfield MJ, et al (2021)

Telomere-to-telomere assembly of the genome of an individual Oikopleura dioica from Okinawa using Nanopore-based sequencing.

BMC genomics, 22(1):222.

BACKGROUND: The larvacean Oikopleura dioica is an abundant tunicate plankton with the smallest (65-70 Mbp) non-parasitic, non-extremophile animal genome identified to date. Currently, there are two genomes available for the Bergen (OdB3) and Osaka (OSKA2016) O. dioica laboratory strains. Both assemblies have full genome coverage and high sequence accuracy. However, a chromosome-scale assembly has not yet been achieved.

RESULTS: Here, we present a chromosome-scale genome assembly (OKI2018_I69) of the Okinawan O. dioica produced using long-read Nanopore and short-read Illumina sequencing data from a single male, combined with Hi-C chromosomal conformation capture data for scaffolding. The OKI2018_I69 assembly has a total length of 64.3 Mbp distributed among 19 scaffolds. 99% of the assembly is contained within five megabase-scale scaffolds. We found telomeres on both ends of the two largest scaffolds, which represent assemblies of two fully contiguous autosomal chromosomes. Each of the other three large scaffolds have telomeres at one end only and we propose that they correspond to sex chromosomes split into a pseudo-autosomal region and X-specific or Y-specific regions. Indeed, these five scaffolds mostly correspond to equivalent linkage groups in OdB3, suggesting overall agreement in chromosomal organization between the two populations. At a more detailed level, the OKI2018_I69 assembly possesses similar genomic features in gene content and repetitive elements reported for OdB3. The Hi-C map suggests few reciprocal interactions between chromosome arms. At the sequence level, multiple genomic features such as GC content and repetitive elements are distributed differently along the short and long arms of the same chromosome.

CONCLUSIONS: We show that a hybrid approach of integrating multiple sequencing technologies with chromosome conformation information results in an accurate de novo chromosome-scale assembly of O. dioica's highly polymorphic genome. This genome assembly opens up the possibility of cross-genome comparison between O. dioica populations, as well as of studies of chromosomal evolution in this lineage.

RevDate: 2021-04-16

Lyu X, Sang PB, W Chai (2021)

CST in maintaining genome stability: Beyond telomeres.

DNA repair, 102:103104.

The human CST (CTC1-STN1-TEN1) complex is an RPA-like single-stranded DNA binding protein complex. While its telomeric functions have been well investigated, numerous studies have revealed that hCST also plays important roles in maintaining genome stability beyond telomeres. Here, we review and discuss recent discoveries on CST in various global genome maintenance pathways, including findings on the CST supercomplex structure, its functions in unperturbed DNA replication, stalled replication, double-strand break repair, and the ATR-CHK1 activation pathway. By summarizing these recent discoveries, we hope to offer new insights into genome maintenance mechanisms and the pathogenesis of CST mutation-associated diseases.

RevDate: 2021-04-13

Gan P, Hiroyama R, Tsushima A, et al (2021)

Telomeres and a repeat-rich chromosome encode effector gene clusters in plant pathogenic Colletotrichum fungi.

Environmental microbiology [Epub ahead of print].

Members of the Colletotrichum gloeosporioides species complex are causal agents of anthracnose in many commercially important plants. Closely related strains have different levels of pathogenicity on hosts despite their close phylogenetic relationship. To gain insight into the genetics underlying these differences, we generated and annotated whole-genome assemblies of multiple isolates of C. fructicola (Cf) and C. siamense (Cs), as well as three previously unsequenced species, C. aenigma (Ca), C. tropicale and C. viniferum with different pathogenicity on strawberry. Based on comparative genomics, we identified accessory regions with a high degree of conservation in strawberry-pathogenic Cf, Cs and Ca strains. These regions encode homologs of pathogenicity-related genes known as effectors, organized in syntenic gene clusters, with copy number variations in different strains of Cf, Cs and Ca. Analysis of highly contiguous assemblies of Cf, Cs and Ca revealed the association of related accessory effector gene clusters with telomeres and repeat-rich chromosomes and provided evidence of exchange between these two genomic compartments. In addition, expression analysis indicated that orthologues in syntenic gene clusters showed a tendency for correlated gene expression during infection. These data provide insight into mechanisms by which Colletotrichum genomes evolve, acquire and organize effectors.

RevDate: 2021-03-30

Saraieva I, Benetos A, Labat C, et al (2021)

Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas.

Frontiers in cell and developmental biology, 9:618335.

Background: Short telomere length (TL) is associated with age-related diseases, in particular cardiovascular diseases. However, whether the onset and course of aortic stenosis (AS) is linked to TL in aortic valves remains unknown.

Objectives: To assess telomere dynamics (TL and telomerase activity) in aortic valves and the possible implication of TL in onset and course of AS.

Methods: DNA was extracted from aortic valves obtained from 55 patients (78.2% men; age, 37-79 years), who had undergone replacement surgery due to AS (AS group, n = 32), aortic valve regurgitation and aortic dilation (Non-AS group, n = 23). TL was measured by telomere restriction fragment analysis (TRF) in calcified and non-calcified aortic valve areas. Telomerase activity was evaluated using telomerase repeat amplification protocol (TRAP) in protein extracts from non-calcified and calcified areas of valves obtained from 4 additional patients (50% men; age, 27-70 years).

Results: TL was shorter in calcified aortic valve areas in comparison to non-calcified areas (n = 31, 8.58 ± 0.73 kb vs. 8.12 ± 0.75 kb, p < 0.0001), whereas telomerase activity was not detected in any of those areas. Moreover, patients from AS group displayed shorter telomeres in non-calcified areas than those from the Non-AS group (8.40 ± 0.64 kb vs. 8.85 ± 0.65, p = 0.01).

Conclusions: Short telomeres in aortic valves may participate in the development of AS, while concurrently the calcification process seems to promote further local decrease of TL in calcified areas of valves.

RevDate: 2021-04-08

Erdem HB, Bahsi T, MA Ergün (2021)

Function of telomere in aging and age related diseases.

Environmental toxicology and pharmacology, 85:103641 pii:S1382-6689(21)00059-4 [Epub ahead of print].

Telomeres consist of specialized non-coding DNA repeat sequences. They are essential for preserving the integrity of the genome during cancer development, senescence. Mammalian telomeres might have 1-50 kb of telomeric DNA, which becomes 40-200 base pairs shorter after per cell cycle, and becomes 5-8 kilobase shorter during senescence. There are many studies on the correlation of telomere length and aging rate. However, as the differences in the methods used in the studies and the scarcity of prospective studies, factors affecting telomere length are not really well understood. Some of the age related diseases may develop due to telomere dysfunction and telomere shortness. The short telomere structure detected in both peripheral blood leukocytes and cells of the disease-related tissue has the feature of being a predictive marker for many age-related diseases. It is expected that with future research, telomere length analysis is expected to enter clinical practice.

RevDate: 2021-04-13

Sepp T, Meitern R, Heidinger B, et al (2021)

Parental age does not influence offspring telomeres during early life in common gulls (Larus canus).

Molecular ecology [Epub ahead of print].

Parental age can affect offspring telomere length through heritable and epigenetic-like effects, but at what stage during development these effects are established is not well known. To address this, we conducted a cross-fostering experiment in common gulls (Larus canus) that enabled us distinguish between pre- and post-natal parental age effects on offspring telomere length. Whole clutches were exchanged after clutch completion within and between parental age classes (young and old) and blood samples were collected from chicks at hatching and during the fastest growth phase (11 days later) to measure telomeres. Neither the ages of the natal nor the foster parents predicted the telomere length or the change in telomere lengths of their chicks. Telomere length (TL) was repeatable within chicks, but increased across development (repeatability = 0.55, intraclass correlation coefficient within sampling events 0.934). Telomere length and the change in telomere length were not predicted by post-natal growth rate. Taken together, these findings suggest that in common gulls, telomere length during early life is not influenced by parental age or growth rate, which may indicate that protective mechanisms buffer telomeres from external conditions during development in this relatively long-lived species.

RevDate: 2021-03-27

Shubin CB, Mayangsari R, Swett AD, et al (2021)

Rif1 regulates telomere length through conserved HEAT repeats.

Nucleic acids research pii:6194407 [Epub ahead of print].

In budding yeast, Rif1 negatively regulates telomere length, but the mechanism of this regulation has remained elusive. Previous work identified several functional domains of Rif1, but none of these has been shown to mediate telomere length. To define Rif1 domains responsible for telomere regulation, we localized truncations of Rif1 to a single specific telomere and measured telomere length of that telomere compared to bulk telomeres. We found that a domain in the N-terminus containing HEAT repeats, Rif1177-996, was sufficient for length regulation when tethered to the telomere. Charged residues in this region were previously proposed to mediate DNA binding. We found that mutation of these residues disrupted telomere length regulation even when Rif1 was tethered to the telomere. Mutation of other conserved residues in this region, which were not predicted to interact with DNA, also disrupted telomere length maintenance, while mutation of conserved residues distal to this region did not. Our data suggest that conserved amino acids in the region from 436 to 577 play a functional role in telomere length regulation, which is separate from their proposed DNA binding function. We propose that the Rif1 HEAT repeats region represents a protein-protein binding interface that mediates telomere length regulation.

RevDate: 2021-03-26

Galli M, Frigerio C, Longhese MP, et al (2021)

The regulation of the DNA damage response at telomeres: focus on kinases.

Biochemical Society transactions pii:228161 [Epub ahead of print].

The natural ends of linear chromosomes resemble those of accidental double-strand breaks (DSBs). DSBs induce a multifaceted cellular response that promotes the repair of lesions and slows down cell cycle progression. This response is not elicited at chromosome ends, which are organized in nucleoprotein structures called telomeres. Besides counteracting DSB response through specialized telomere-binding proteins, telomeres also prevent chromosome shortening. Despite of the different fate of telomeres and DSBs, many proteins involved in the DSB response also localize at telomeres and participate in telomere homeostasis. In particular, the DSB master regulators Tel1/ATM and Mec1/ATR contribute to telomere length maintenance and arrest cell cycle progression when chromosome ends shorten, thus promoting a tumor-suppressive process known as replicative senescence. During senescence, the actions of both these apical kinases and telomere-binding proteins allow checkpoint activation while bulk DNA repair activities at telomeres are still inhibited. Checkpoint-mediated cell cycle arrest also prevents further telomere erosion and deprotection that would favor chromosome rearrangements, which are known to increase cancer-associated genome instability. This review summarizes recent insights into functions and regulation of Tel1/ATM and Mec1/ATR at telomeres both in the presence and in the absence of telomerase, focusing mainly on discoveries in budding yeast.

RevDate: 2021-04-07

Lagnado A, Leslie J, Ruchaud-Sparagano MH, et al (2021)

Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner.

The EMBO journal [Epub ahead of print].

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.

RevDate: 2021-03-26

Li Y, Cheang I, Zhang Z, et al (2021)

Prognostic Association of TERC, TERT Gene Polymorphism, and Leukocyte Telomere Length in Acute Heart Failure: A Prospective Study.

Frontiers in endocrinology, 12:650922.

Background: Telomere length and telomerase are associated in development of cardiovascular diseases. Study aims to investigate the associations of TERC and TERT gene polymorphism and leukocyte telomere length (LTL) in the prognosis of acute heart failure (AHF).

Methods: Total 322 patients with AHF were enrolled and divided into death and survival group according to all-cause mortality within 18 months. Seven single nucleotide polymorphisms (SNPs) of TERC and TERT were selected. Baseline characteristics, genotype distribution and polymorphic allele frequency, and genetic model were initially analyzed. Genotypes and the LTL were determined for further analysis.

Results: Compared to carrying homozygous wild genotype, the risk of death in patients with mutated alleles of four SNPs- rs12696304(G>C), rs10936599(T>C), rs1317082(G>A), and rs10936601(T>C) of TERC were significantly higher. The dominant models of above were independently associated with mortality. In recessive models, rs10936599 and rs1317082 of TERC, rs7726159 of TERT were independently associated with long-term mortality. Further analysis showed, in haplotype consisting with TERC - rs12696304, rs10936599, rs1317082, and rs10936601, mutant alleles CCAC and wild alleles GTGT were significant difference between groups (P<0.05). CCAC is a risk factor and GTGT is a protective factor for AHF patients. Relative LTL decreased over age, but showed no difference between groups and genotypes.

Conclusions: The SNPs of TERC and TERT are associated with the prognosis of AHF, and are the independent risk factors for predicting 18-month mortality in AHF.

RevDate: 2021-03-25

Yamada S, Misawa K, Mima M, et al (2021)

Telomere shortening in head and neck cancer: association between DNA demethylation and survival.

Journal of Cancer, 12(8):2165-2172.

A growing body of evidence indicates that telomere dysfunction is a biological marker of progression in several types of cancer. However, the association between head and neck squamous cell carcinoma (HNSCC) and telomere length (TL) remains unknown. We measured the absolute TL levels in a well-characterised dataset of 211 tumoral vs normal tissues obtained from the same patients by quantitative polymerase chain reaction assay. Normalised TL levels were significantly lower in tumour samples than in normal tissue (P < 0.001) and there was a positive correlation between tumour tissue and normal mucosal tissue (R2 = 0.176, P < 0.001). We were able to distinguish two classes, one with a tumour/normal TL ratio ≤ 0.3 (38.4%), which showed clear telomere erosion, and the other with a tumour/normal TL ratio > 0.3 (61.6%), in which the TL was slightly shorter or longer than that in normal tissue. Notably, the tumour/normal TL ratio was correlated with the likelihood of disease recurrence (P = 0.002), the 5-hydroxymethylcytosine level (P = 0.043), and expression of the ten-eleven translocation (TET) gene (P = 0.043). Our findings show that TL shortening and subsequent low levels of 5-hydroxymethylcytosine and TET expression may contribute to development of HNSCC.

RevDate: 2021-04-01

Cai Y, Liu H, Song E, et al (2021)

Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling.

Theranostics, 11(10):4710-4727.

Background: Telomere shortening and dysfunction may cause metabolic disorders, tissue damage and age-dependent pathologies. However, little is known about the association of telomere-associated protein Rap1 with mitochondrial energy metabolism and cardiac aging. Methods: Echocardiography was performed to detect cardiac structure and function in Rap1+/+ and Rap1-/- mice at different ages (3 months, 12 months and 20 months). Telomere length, DNA damage, cardiac senescence and cardiomyocyte size were analyzed using the real-time PCR, Western blotting, senescence associated β-galactosidase assay and wheat germ agglutinin staining, respectively. Western blotting was also used to determine the level of cardiac fatty acid metabolism related key enzymes in mouse and human myocardium. Chromatin immunoprecipitation assay was used to verify the direct link between p53 and PPARα. The p53 inhibitor, Pifithrin-α and PPARα activator WY14643 were utilized to identify the effects of Rap1/p53/PPARα signaling pathway. Results: Telomere was shortened concomitant with extensive DNA damage in aged Rap1-/- mouse hearts, evidenced by reduced T/S ratios and increased nuclear γH2AX. Meanwhile, the aging-associated phenotypes were pronounced as reflected by altered mitochondrial ultrastructure, enhanced senescence, cardiac hypertrophy and dysfunction. Mechanistically, acetylated p53 and nuclear p53 was enhanced in the Rap1-/- mouse hearts, concomitant with reduced PPARα. Importantly, p53 directly binds to the promoter of PPARα in mouse hearts and suppresses the transcription of PPARα. In addition, aged Rap1-/- mice exhibited reduced cardiac fatty acid metabolism. Pifithrin-α alleviated cardiac aging and enhanced fatty acid metabolism in the aged Rap1-/- mice. Activating PPARα with WY14643 in primarily cultured Rap1-/- cardiomyocytes restored maximal oxygen consumption rates. Reduced Rap1 expression and impaired p53/PPARα signaling also presented in aged human myocardium. Conclusion: In summary, Rap1 may link telomere biology to fatty acid metabolism and aging-related cardiac pathologies via modulating the p53/PPARα signaling pathway, which could represent a therapeutic target in preventing/attenuating cardiac aging.

RevDate: 2021-04-12
CmpDate: 2021-04-12

Lyčka M, Peska V, Demko M, et al (2021)

WALTER: an easy way to online evaluate telomere lengths from terminal restriction fragment analysis.

BMC bioinformatics, 22(1):145.

BACKGROUND: Telomeres, nucleoprotein structures comprising short tandem repeats and delimiting the ends of linear eukaryotic chromosomes, play an important role in the maintenance of genome stability. Therefore, the determination of the length of telomeres is of high importance for many studies. Over the last years, new methods for the analysis of the length of telomeres have been developed, including those based on PCR or analysis of NGS data. Despite that, terminal restriction fragment (TRF) method remains the gold standard to this day. However, this method lacks universally accepted and precise tool capable to analyse and statistically evaluate TRF results.

RESULTS: To standardize the processing of TRF results, we have developed WALTER, an online toolset allowing rapid, reproducible, and user-friendly analysis including statistical evaluation of the data. Given its web-based nature, it provides an easily accessible way to analyse TRF data without any need to install additional software.

CONCLUSIONS: WALTER represents a major upgrade from currently available tools for the image processing of TRF scans. This toolset enables a rapid, highly reproducible, and user-friendly evaluation of almost any TRF scan including in-house statistical evaluation of the data. WALTER platform together with user manual describing the evaluation of TRF scans in detail and presenting tips and troubleshooting, as well as test data to demo the software are available at https://www.ceitec.eu/chromatin-molecular-complexes-jiri-fajkus/rg51/tab?tabId=125#WALTER and the source code at https://github.com/mlyc93/WALTER .

RevDate: 2021-03-25

Young RC, Kitaysky AS, HM Drummond (2021)

Telomere lengths correlate with fitness but assortative mating by telomeres confers no benefit to fledgling recruitment.

Scientific reports, 11(1):5463.

Assortative mating by telomere lengths has been observed in several bird species, and in some cases may increase fitness of individuals. Here we examined the relationship between telomere lengths of Blue-footed Booby (Sula nebouxii) mates, long-lived colonial seabirds with high annual divorce rates. We tested the hypothesis that interactions between maternal and paternal telomere lengths affect offspring and parental survival. We found that relative telomere lengths (RTL) were strongly positively correlated between members of a breeding pair. In addition, RTL of both parents interacted to predict fledgling recruitment, although fledglings with two very long-RTL parents performed only averagely. Telomere lengths also predicted adult survival: birds with long telomeres were more likely to survive, but birds whose mate had long telomeres were less likely to survive. Thus, having long telomeres benefits survival, while choosing a mate with long telomeres benefits reproductive output while penalizing survival. These patterns demonstrate that while a breeder's RTL predicts offspring quality, assortative mating by RTL does not enhance fitness, and a trade-off between different components of fitness may govern patterns of assortative mating by telomere length. They also illustrate how testing the adaptive value of only one parent's telomere length on either survival or reproductive success alone may provide equivocal results.

RevDate: 2021-04-16
CmpDate: 2021-04-16

Godwin LS, Bridger JM, HA Foster (2021)

Fluorescence In Situ Hybridization on DNA Halo Preparations to Reveal Whole Chromosomes, Telomeres and Gene Loci.

Journal of visualized experiments : JoVE.

The genome is associated with several structures inside cell nuclei, in order to regulate its activity and anchor it in specific locations. These structures are collectively known as the nucleoskeleton and include the nuclear lamina, the nucleoli, and nuclear bodies. Although many variants of fluorescence in situ hybridization (FISH) exist to study the genome and its organization, these are often limited by resolution and provide insufficient information on the genome's association with nuclear structures. The DNA halo method uses high salt concentrations and nonionic detergents to generate DNA loops that remain anchored to structures within nuclei through attachment regions within the genome. Here, soluble nuclear proteins, such as histones, lipids, and DNA not tightly bound to the nuclear matrix, are extracted. This leads to the formation of a halo of unattached DNA surrounding a residual nucleus which itself contains DNA closely associated with internal nuclear structures and extraction-resistant proteins. These extended DNA strands enable increased resolution and can facilitate physical mapping. In combination with FISH, this method has the added advantage of studying genomic interactions with all the structures that the genome is anchored by. This technique, termed HALO-FISH, is highly versatile whereby DNA halos can be coupled with nucleic acid probes to reveal gene loci, whole chromosomes, alpha satellite, telomeres and even RNA. This technique provides an insight into nuclear organization and function in normal cells and in disease progression such as with cancer.

RevDate: 2021-03-22

Ismail H, Helby J, Hölmich LR, et al (2021)

Genetic predisposition to long telomeres is associated with increased mortality after melanoma: a study of 2101 melanoma patients from hospital clinics and the general population.

Pigment cell & melanoma research [Epub ahead of print].

Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypotheses that measured and genetically predicted telomere length are associated with mortality after a melanoma diagnosis. We followed 2101patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC) and rs2487999 (OBFC1);all three genotypes are associated with telomere length, and combined into an allele count from 0 to 6. For each telomere-lengthening allele, the hazard ratios (HR) for mortality in the age-adjusted and multivariable adjusted Cox analysis were 1.12 (95% confidence interval: 1.02 - 1.23) and 1.11 (1.01 - 1.23).However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88 - 1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not.

RevDate: 2021-04-15

Adam N, Beattie TL, K Riabowol (2021)

Fluorescence microscopy methods for examining telomeres during cell aging.

Ageing research reviews, 68:101320 pii:S1568-1637(21)00067-2 [Epub ahead of print].

Telomeres are protective structures, composed of nucleic acids and a complex protein mixture, located at the end of the chromosomes. They play an important role in preventing genomic instability and ensuring cell health. Defects in telomere integrity result in cell dysfunction and the development of diseases, including neurodegenerative disorders, cancer and premature aging syndromes, among others. Loss of telomere integrity during normal cell aging also initiates DNA damage signals that culminate in the senescence phenotype. Fluorescence microscopy has allowed researchers to study the dynamics, shape, localization, and co-distribution of telomeres with proteins of interest. The microscopy tools to investigate these structures have evolved, making it possible to understand in greater detail the molecular mechanisms affecting telomeres that contribute to cell aging and the development of age-related diseases. Using human fibroblasts as an example, we will highlight several characteristics of telomeres that can be investigated using three different microscopy systems, including wide-field microscopy, and the two super-resolution techniques called 3D Structured Illumination Microscopy (3D-SIM) and direct Stochastic Optical Reconstruction Microscopy (dSTORM). In this review, we will also discuss their limitations and highlight their importance in answering telomere-related scientific questions.

RevDate: 2021-04-13

Beier F, Esser A, Vankann L, et al (2021)

Longitudinal changes in telomere length in PCB-exposed individuals: interaction with CMV infection.

Archives of toxicology, 95(4):1517-1520.

We recently demonstrated a significant shortening of age-adapted telomere length (TL) in lymphocytes of polychlorinated biphenyls (PCB)-exposed individuals. Here, we analyzed TL in individuals of the same PCB-exposed cohort during a 6-year follow-up period, investigating the change in TL between the first and second measurement as a function of time, concentration of PCBs and cytomegalovirus (CMV) infection. The age-adjusted TL of lymphocytes within the cohort of PCB-exposed individuals recovered from a first assessment in 2011 to a second assessment in 2017. Remarkably, if the concentration of lower chlorinated PCBs (LC PCBs) in 2011 was high (≥ 0.055 µg/L), the TL of CMV seropositive individuals remained significantly shortened both compared to age-adjusted controls as well as intra individually. This was confirmed by analysis of covariance as well as by multivariate linear mixed effects models. Since telomeres are responsive to various stress response pathways, including viral infection, we conclude that PCBs could contribute to immune senescence-like phenotypes associated with CMV infections and exacerbate negative aspects associated with the aging of the immune system.

RevDate: 2021-03-19

Brown DW, Lan Q, Rothman N, et al (2021)

Genetically inferred telomere length and testicular germ cell tumor risk.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1775 [Epub ahead of print].

BACKGROUND: Studies evaluating the association between peripheral blood leukocyte telomere length and testicular germ cell tumor (TGCT) risk have produced conflicting results.

METHODS: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score (PRS) and mendelian randomization (MR) analyses of genetic variants previously associated with leukocyte telomere length were used to assess potential etiologic associations between telomere length and TGCT risk.

RESULTS: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (odds ratio (OR)=1.02, 95% confidence interval (CI)= 0.97-1.07). MR analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC consortium participants (3,558 cases; 13,971 controls).

CONCLUSIONS: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood leukocyte telomere length and TGCT risk.

IMPACT: The lack of evidence for an overall association indicates that peripheral blood leukocyte telomere length is likely not a strong biomarker for TGCT risk.

RevDate: 2021-03-18

Welendorf CR, Nicoletti CF, Noronha NY, et al (2021)

The Impact of Gastric Bypass on Telomere Length and Shelterin Complex Gene Expression: 6 Months Prospective Study.

Obesity surgery [Epub ahead of print].

BACKGROUND: Telomeres are structures located at the ends of chromosomes associated with a protein complex, known as the shelterin complex. In individuals with obesity, excess adipose tissue plays a key role in inducing a chronic and systemic inflammatory state, which can cause TL shortening. In this context, bariatric surgery is one of the most effective treatment modalities in improving metabolic control.

AIM: Therefore, the present study aimed to evaluate how a short postoperative period of gastric bypass affects TL and expression of POT1, TRF1 and TRF2 genes.

METHODS: Forty-eight women submitted to RYGB were evaluated before and after 6 months of the surgical procedure. Anthropometric measures of body weight and height (BMI), abdominal circumference (AC), body composition, food intake and blood collection for biochemical evaluation, TL analysis (DNA), and gene expression (RNA) were collected at each moment.

RESULTS: There was a reduction of weight, BMI, AC, FM and FFM as well as of glycemia, total cholesterol, LDL-cholesterol, and triglycerides after gastric bypass. No difference in energy intake and macronutrients consumption was observed. There was no significant change in TL, but there was a significant increase of POT1 and TRF1 gene expression after surgery, while TRF2 expression did not change.

CONCLUSIONS: Despite bariatric surgery is not capable of increasing telomere length in a short-term period, no reduction is observed; additionally, we found a correlation between serum triglycerides concentration and TL. The increase of POT1 and TRF1 gene expression may explain the maintenance of the TL after 6 months postoperative period.

RevDate: 2021-03-20

Doroschuk NA, Postnov AY, Doroschuk AD, et al (2021)

An original biomarker for the risk of developing cardiovascular diseases and their complications: Telomere length.

Toxicology reports, 8:499-504.

Aim: The aim of this work was to study the effect of telomere length in the chromosomes of nuclear blood cells in individuals with coronary heart disease (CHD) on the development of cardiovascular complications (CVC).

Materials and methods: DNA was isolated from nuclear blood cells of 498 study participants. The telomere length was determined by real-time polymerase chain reaction. The investigation of each sample was repeated three times. Five years after the end of this study, a telephone survey of 119 patients with CHD was conducted in order to obtain data on the presence of CVC.

Results: According to the results obtained, a decrease in telomere length in patients with coronary heart disease increases the risk of subsequent development of cardiovascular complications.

Conclusion: Patients with coronary heart disease with shorter telomeres compared with conventionally healthy study participants had an increased risk of cardiovascular complications within 5 years after telomere analysis.

RevDate: 2021-03-20

Sibert NT, Ventura Ferreira MS, Wagner W, et al (2021)

Cord blood telomere shortening associates with increased gestational age and birth weight in preterm neonates.

Experimental and therapeutic medicine, 21(4):344.

Preterm birth is considered to be associated with premature cellular aging. To address this question, two hallmarks of aging were analyzed in cord blood cells, namely telomere length and age-associated DNA methylation. Cord blood samples from 35 preterm and 11 full-term neonates were enrolled in the present study. Furthermore, quantitative telomere fluorescence in situ hybridization and flow cytometry (flow-FISH) were applied to demonstrate that telomere shortening was strongly associated with advanced gestational age and increased birth weight (R2=0.267 for granulocytes and R2=0.307 for lymphocytes). The estimated rate of telomere attrition in newborns during gestation ranged from 126 base pairs (bp)/week and 186 bp/week for granulocytes and lymphocytes, respectively. In addition, neonates with longer telomeres at birth were characterized by increased weight gain during the first year of their life compared with that noted to neonates with shorter telomeres. By contrast, the epigenetic aging signature (EAS) revealed a negative correlation between epigenetic age and premature birth of unclear basis (R2=0.26). Pending prospective validation in a larger patient cohort, the present study suggested that telomere length may be a novel biomarker alone or in combination with traditional indicators for the prediction of weight development in preterm neonates.

RevDate: 2021-03-31

Boonekamp J, Rodríguez-Muñoz R, Hopwood P, et al (2021)

Telomere length is highly heritable and independent of growth rate manipulated by temperature in field crickets.

Molecular ecology [Epub ahead of print].

Many organisms are capable of growing faster than they do. Restrained growth rate has functionally been explained by negative effects on lifespan of accelerated growth. However, the underlying mechanisms remain elusive. Telomere attrition has been proposed as a causal agent and has been mostly studied in endothermic vertebrates. We established that telomeres exist as chromosomal-ends in a model insect, the field cricket Gryllus campestris, using terminal restriction fragment and Bal 31 methods. Telomeres comprised TTAGGn repeats of 38 kb on average, more than four times longer than the telomeres of human infants. Bal 31 assays confirmed that telomeric repeats were located at the chromosome-ends. We tested whether rapid growth between day 1, day 65, day 85, and day 125 is achieved at the expense of telomere length by comparing nymphs reared at 23°C with their siblings reared at 28°C, which grew three times faster in the initial 65 days. Surprisingly, neither temperature treatment nor age affected average telomere length. Concomitantly, the broad sense heritability of telomere length was remarkably high at ~100%. Despite high heritability, the evolvability (a mean-standardized measure of genetic variance) was low relative to that of body mass. We discuss our findings in the context of telomere evolution. Some important features of vertebrate telomere biology are evident in an insect species dating back to the Triassic. The apparent lack of an effect of growth rate on telomere length is puzzling, suggesting strong telomere length maintenance during the growth phase. Whether such maintenance of telomere length is adaptive remains elusive and requires further study investigating the links with fitness in the wild.

RevDate: 2021-03-17

Espigares F, Abad-Tortosa D, Varela SAM, et al (2021)

Short telomeres drive pessimistic judgement bias in zebrafish.

Biology letters, 17(3):20200745.

The role of telomerase reverse transcriptase has been widely investigated in the contexts of ageing and age-related diseases. Interestingly, decreased telomerase activities (and accelerated telomere shortening) have also been reported in patients with emotion-related disorders, opening the possibility for subjective appraisal of stressful stimuli playing a key role in stress-driven telomere shortening. In fact, patients showing a pessimistic judgement bias have shorter telomeres. However, in humans the evidence for this is correlational and the causal directionality between pessimism and telomere shortening has not been established experimentally yet. We have developed and validated a judgement bias experimental paradigm to measure subjective evaluations of ambiguous stimuli in zebrafish. This behavioural assay allows classification of individuals in an optimistic-pessimistic dimension (i.e. from individuals that consistently evaluate ambiguous stimuli as negative to others that perceive them as positive). Using this behavioural paradigm we found that telomerase-deficient zebrafish (tert- /-) were more pessimistic in response to ambiguous stimuli than wild-type zebrafish. The fact that individuals with constitutive shorter telomeres have pessimistic behaviours demonstrates for the first time in a vertebrate model a genetic basis of judgement bias.

RevDate: 2021-03-17

McGurk MP, Dion-Côté AM, DA Barbash (2021)

Rapid evolution at the Drosophila telomere: transposable element dynamics at an intrinsically unstable locus.

Genetics, 217(2):.

Drosophila telomeres have been maintained by three families of active transposable elements (TEs), HeT-A, TAHRE, and TART, collectively referred to as HTTs, for tens of millions of years, which contrasts with an unusually high degree of HTT interspecific variation. While the impacts of conflict and domestication are often invoked to explain HTT variation, the telomeres are unstable structures such that neutral mutational processes and evolutionary tradeoffs may also drive HTT evolution. We leveraged population genomic data to analyze nearly 10,000 HTT insertions in 85 Drosophila melanogaster genomes and compared their variation to other more typical TE families. We observe that occasional large-scale copy number expansions of both HTTs and other TE families occur, highlighting that the HTTs are, like their feral cousins, typically repressed but primed to take over given the opportunity. However, large expansions of HTTs are not caused by the runaway activity of any particular HTT subfamilies or even associated with telomere-specific TE activity, as might be expected if HTTs are in strong genetic conflict with their hosts. Rather than conflict, we instead suggest that distinctive aspects of HTT copy number variation and sequence diversity largely reflect telomere instability, with HTT insertions being lost at much higher rates than other TEs elsewhere in the genome. We extend previous observations that telomere deletions occur at a high rate, and surprisingly discover that more than one-third do not appear to have been healed with an HTT insertion. We also report that some HTT families may be preferentially activated by the erosion of whole telomeres, implying the existence of HTT-specific host control mechanisms. We further suggest that the persistent telomere localization of HTTs may reflect a highly successful evolutionary strategy that trades away a stable insertion site in order to have reduced impact on the host genome. We propose that HTT evolution is driven by multiple processes, with niche specialization and telomere instability being previously underappreciated and likely predominant.

RevDate: 2021-03-16

Cherdyntseva V, S Gagos (2021)

Corrigendum to: "Chromosome extremities under the microscopy lens: molecular cytogenetics in telomere research". [Curr Opin Genet Dev. 2020; 60:69-76].

Current opinion in genetics & development, 66:110-111.

RevDate: 2021-03-17
CmpDate: 2021-03-17

Doroshchuk NA, Lankin VZ, Tikhaze AK, et al (2021)

[Telomere length as a biomarker of the risk of cardiovascular complications in patients with coronary heart disease].

Terapevticheskii arkhiv, 93(1):20-24.

AIM: To study the effect of oxidative stress and telomere length in the chromosomes of blood leukocytes in patients with coronary heart disease (CHD) on the development of cardiovascular complications.

MATERIALS AND METHODS: In 119 patients with CHD, the level of oxidatively modified low-density lipoproteins (ox-LDL) in blood plasma and the length of telomeres in nuclear blood cells were determined during the examination. After 5 years, a telephone survey of patients (or their relatives) was conducted to obtain data on the presence of cardiovascular complications. Telomere length was determined using quantitative real-time PCR, and the level of ox-LDL was determined by immunochemical method.

RESULTS: It was found that reducing the length of telomeres in patients with CHD increases the risk of subsequent development of cardiovascular complications. A strong negative correlation was found between the level of ox-LDL and telomere length in the group of examined CHD patients who had cardiovascular complications after 5 years.

CONCLUSION: CHD patients with short telomere length and high levels of ox-LDL have an increased risk of cardiovascular complications during 5 years.

RevDate: 2021-03-15

Garfein J, Flannagan KS, Rittman D, et al (2021)

Leukocyte telomere length is inversely associated with a metabolic risk score in Mesoamerican children.

American journal of human biology : the official journal of the Human Biology Council [Epub ahead of print].

OBJECTIVE: Leukocyte telomere length (LTL) may be involved in the etiology of the metabolic syndrome (MetS). We examined the associations of LTL with MetS and its components among Mesoamerican children and their adult parents, in a region where MetS prevalence is high.

METHODS: We conducted a cross-sectional study of 151 children aged 7-12 years and 346 parents from the capitals of Belize, Honduras, Nicaragua, Costa Rica, Panama, and Chiapas State, Mexico. We quantified LTL by qPCR on DNA extracted from whole blood. In children, we created an age- and sex-standardized metabolic risk score using waist circumference (WC), the homeostasis model of insulin resistance (HOMA-IR), blood pressure, serum high-density lipoprotein (HDL) cholesterol, and serum triglycerides. In adults, MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III definition. We estimated mean differences in metabolic risk score and prevalence ratios of MetS across quartiles of LTL using multivariable-adjusted linear and Poisson regression models, respectively.

RESULTS: In children, every 1 LTL z-score was related to an adjusted 0.05 units lower (95% CI: -0.09, -0.02, P = 0.005) MetS risk score, through WC, HOMA-IR, and HDL. Among adults, LTL was not associated with MetS prevalence; however, every 1 LTL z-score was associated with an adjusted 34% lower prevalence of high fasting glucose (95% CI: 3%, 55%, p = .03).

CONCLUSIONS: Among Mesoamerican children, LTL is associated with an improved metabolic profile; among adults, LTL is inversely associated with the prevalence of high fasting glucose.

RevDate: 2021-03-16

Lue NF (2021)

Duplex Telomere-Binding Proteins in Fungi With Canonical Telomere Repeats: New Lessons in the Rapid Evolution of Telomere Proteins.

Frontiers in genetics, 12:638790.

The telomere protein assemblies in different fungal lineages manifest quite profound structural and functional divergence, implying a high degree of flexibility and adaptability. Previous comparative analyses of fungal telomeres have focused on the role of telomere sequence alterations in promoting the evolution of corresponding proteins, particularly in budding and fission yeast. However, emerging evidence suggests that even in fungi with the canonical 6-bp telomere repeat unit, there are significant remodeling of the telomere assembly. Indeed, a new protein family can be recruited to serve dedicated telomere functions, and then experience subsequent loss in sub-branches of the clade. An especially interesting example is the Tay1 family of proteins, which emerged in fungi prior to the divergence of basidiomycetes from ascomycetes. This relatively recent protein family appears to have acquired its telomere DNA-binding activity through the modification of another Myb-containing protein. Members of the Tay1 family evidently underwent rather dramatic functional diversification, serving, e.g., as transcription factors in fission yeast while acting to promote telomere maintenance in basidiomycetes and some hemi-ascomycetes. Remarkably, despite its distinct structural organization and evolutionary origin, a basidiomycete Tay1 appears to promote telomere replication using the same mechanism as mammalian TRF1, i.e., by recruiting and regulating Blm helicase activity. This apparent example of convergent evolution at the molecular level highlight the ability of telomere proteins to acquire new interaction targets. The remarkable evolutionary history of Tay1 illustrates the power of protein modularity and the facile acquisition of nucleic acid/protein-binding activity to promote telomere flexibility.

RevDate: 2021-04-01
CmpDate: 2021-04-01

Baxley RM, Leung W, Schmit MM, et al (2021)

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.

Nature communications, 12(1):1626.

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

RevDate: 2021-04-01
CmpDate: 2021-04-01

Shiromoto Y, Sakurai M, Minakuchi M, et al (2021)

ADAR1 RNA editing enzyme regulates R-loop formation and genome stability at telomeres in cancer cells.

Nature communications, 12(1):1654.

ADAR1 is involved in adenosine-to-inosine RNA editing. The cytoplasmic ADAR1p150 edits 3'UTR double-stranded RNAs and thereby suppresses induction of interferons. Loss of this ADAR1p150 function underlies the embryonic lethality of Adar1 null mice, pathogenesis of the severe autoimmune disease Aicardi-Goutières syndrome, and the resistance developed in cancers to immune checkpoint blockade. In contrast, the biological functions of the nuclear-localized ADAR1p110 remain largely unknown. Here, we report that ADAR1p110 regulates R-loop formation and genome stability at telomeres in cancer cells carrying non-canonical variants of telomeric repeats. ADAR1p110 edits the A-C mismatches within RNA:DNA hybrids formed between canonical and non-canonical variant repeats. Editing of A-C mismatches to I:C matched pairs facilitates resolution of telomeric R-loops by RNase H2. This ADAR1p110-dependent control of telomeric R-loops is required for continued proliferation of telomerase-reactivated cancer cells, revealing the pro-oncogenic nature of ADAR1p110 and identifying ADAR1 as a promising therapeutic target of telomerase positive cancers.

RevDate: 2021-04-08

Fernandes SG, Dsouza R, E Khattar (2021)

External environmental agents influence telomere length and telomerase activity by modulating internal cellular processes: Implications in human aging.

Environmental toxicology and pharmacology, 85:103633 pii:S1382-6689(21)00051-X [Epub ahead of print].

External environment affects cellular physiological processes and impact the stability of our genome. The most important structural components of our linear chromosomes which endure the impact by these agents, are the chromosomal ends called telomeres. Telomeres preserve the integrity of our genome by preventing end to end fusions and telomeric loss through by inhibiting DNA damage response (DDR) activation. This is accomplished by the presence of a six membered shelterin complex at telomeres. Further, telomeres cannot be replicated by normal DNA polymerase and require a special enzyme called telomerase which is expressed only in stem cells, few immune cells and germ cells. Telomeres are rich in guanine content and thus become extremely prone to damage arising due to physiological processes like oxidative stress and inflammation. External environmental factors which includes various physical, biological and chemical agents also affect telomere homeostasis by increasing oxidative stress and inflammation. In the present review, we highlight the effect of these external factors on telomerase activity and telomere length. We also discuss how the external agents affect the physiological processes, thus modulating telomere stability. Further, we describe its implication in the development of aging and its related pathologies.

RevDate: 2021-03-12

Lesmana A, Tian P, Karlaftis V, et al (2021)

Continuous reference intervals for leukocyte telomere length in children: the method matters.

Clinical chemistry and laboratory medicine pii:cclm-2021-0059 [Epub ahead of print].

OBJECTIVES: Children with very short telomeres commonly develop bone marrow failure and other severe diseases. Identifying the individuals with short telomeres can improve outcome of bone marrow transplantation, with accurate diagnosis requiring the use of age-matched reference intervals (RIs). This study aimed to establish RIs for telomere length (TL) in children using three commonly used methods for TL measurement.

METHODS: Healthy children aged 30 days to 18 years were recruited for assessment using age as a continuous variable. Venous blood samples were collected and leukocyte TL was measured using terminal restriction fragment (TRF) analysis, quantitative PCR (QPCR) and flow cytometry with fluorescence in situ hybridization (Flow-FISH). Fractional polynomial model and quantile regression were performed to generate continuous RIs. Factors that might contribute to variation in TL, such as gender, were also examined.

RESULTS: A total of 212 samples were analyzed. Continuous RIs are presented as functions of age. TRF analysis and QPCR showed significant negative correlation between TL and age (r=-0.28 and r=-0.38, p<0.001). In contrast, Flow-FISH showed no change in TL with age (r=-0.08, p=0.23). Gender did not have significant influence on TL in children.

CONCLUSIONS: This study provides three options to assess TL in children by establishing method-specific continuous RIs. Choosing which method to use will depend on several factors such as amount and type of sample available and required sensitivity to age-related change.

RevDate: 2021-04-12

Mizuno T, Hirabayashi K, Miyazawa S, et al (2021)

The intrinsically disordered N-terminal region of mouse DNA polymerase alpha mediates its interaction with POT1a/b at telomeres.

Genes to cells : devoted to molecular & cellular mechanisms [Epub ahead of print].

Mouse telomerase and the DNA polymerase alpha-primase complex elongate the leading and lagging strands of telomeres, respectively. To elucidate the molecular mechanism of lagging strand synthesis, we investigated the interaction between DNA polymerase alpha and two paralogs of the mouse POT1 telomere-binding protein (POT1a and POT1b). Yeast two-hybrid analysis and a glutathione S-transferase pull-down assay indicated that the C-terminal region of POT1a/b binds to the intrinsically disordered N-terminal region of p180, the catalytic subunit of mouse DNA polymerase alpha. Subcellular distribution analyses showed that although POT1a, POT1b, and TPP1 were localized to the cytoplasm, POT1a-TPP1 and POT1b-TPP1 coexpressed with TIN2 localized to the nucleus in a TIN2 dose-dependent manner. Coimmunoprecipitation and cell cycle synchronization experiments indicated that POT1b-TPP1-TIN2 was more strongly associated with p180 than POT1a-TPP1-TIN2, and this complex accumulated during the S phase. Fluorescence in situ hybridization and proximity ligation assays showed that POT1a and POT1b interacted with p180 and TIN2 on telomeric chromatin. Based on the present study and a previous study, we propose a model in which POT1a/b-TPP1-TIN2 translocates into the nucleus in a TIN2 dose-dependent manner to target the telomere, where POT1a/b interacts with DNA polymerase alpha for recruitment at the telomere for lagging strand synthesis.

RevDate: 2021-03-12

Norris K, Walne AJ, Ponsford MJ, et al (2021)

High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders.

Human genetics [Epub ahead of print].

Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.

RevDate: 2021-03-17

Anonymous (2021)

Corrigendum for Vahter et al. Placental and Cord Blood Telomere Length in Relation to Maternal Nutritional Status. J Nutr 2020;150(10):2646-55, https://doi.org/10.1093/jn/nxaa198.

The Journal of nutrition, 151(3):742.

RevDate: 2021-04-12

Mustafa G, Shiekh S, Gc K, et al (2021)

Interrogating accessibility of telomeric sequences with FRET-PAINT: evidence for length-dependent telomere compaction.

Nucleic acids research, 49(6):3371-3380.

Single-stranded telomeric overhangs are ∼200 nucleotides long and can form tandem G-quadruplex (GQ) structures, which reduce their accessibility to nucleases and proteins that activate DNA damage response. Whether these tandem GQs further stack to form compact superstructures, which may provide better protection for longer telomeres, is not known. We report single-molecule measurements where the accessibility of 24-144 nucleotide long human telomeric DNA molecules is interrogated by a short PNA molecule that is complementary to a single GGGTTA repeat, as implemented in the FRET-PAINT method. Binding of the PNA strand to available GGGTTA sequences results in discrete FRET bursts which were analyzed in terms of their dwell times, binding frequencies, and topographic distributions. The binding frequencies were greater for binding to intermediate regions of telomeric DNA compared to 3'- or 5'-ends, suggesting these regions are more accessible. Significantly, the binding frequency per telomeric repeat monotonically decreased with increasing telomere length. These results are consistent with telomeres forming more compact structures at longer lengths, reducing accessibility of these critical genomic sites.

RevDate: 2021-04-12

Kim E, Kim J, Kim C, et al (2021)

Long-read sequencing and de novo genome assemblies reveal complex chromosome end structures caused by telomere dysfunction at the single nucleotide level.

Nucleic acids research, 49(6):3338-3353.

Karyotype change and subsequent evolution is triggered by chromosome fusion and rearrangement events, which often occur when telomeres become dysfunctional. Telomeres protect linear chromosome ends from DNA damage responses (DDRs), and telomere dysfunction may result in genome instability. However, the complex chromosome end structures and the other possible consequences of telomere dysfunction have rarely been resolved at the nucleotide level due to the lack of the high-throughput methods needed to analyse these highly repetitive regions. Here we applied long-read sequencing technology to Caenorhabditis elegans survivor lines that emerged after telomere dysfunction. The survivors have preserved traces of DDRs in their genomes and our data revealed that variants generated by telomere dysfunction are accumulated along all chromosomes. The reconstruction of the chromosome end structures through de novo genome assemblies revealed diverse types of telomere damage processing at the nucleotide level. When telomeric repeats were totally eroded by telomere dysfunction, DDRs were mostly terminated by chromosome fusion events. We also partially reconstructed the most complex end structure and its DDR signatures, which would have been accumulated via multiple cell divisions. These finely resolved chromosome end structures suggest possible mechanisms regarding the repair processes after telomere dysfunction, providing insights into chromosome evolution in nature.

RevDate: 2021-03-20

Seeker LA, Underwood SL, Wilbourn RV, et al (2021)

Telomere attrition rates are associated with weather conditions and predict productive lifespan in dairy cattle.

Scientific reports, 11(1):5589.

Telomere length is predictive of adult health and survival across vertebrate species. However, we currently do not know whether such associations result from among-individual differences in telomere length determined genetically or by early-life environmental conditions, or from differences in the rate of telomere attrition over the course of life that might be affected by environmental conditions. Here, we measured relative leukocyte telomere length (RLTL) multiple times across the entire lifespan of dairy cattle in a research population that is closely monitored for health and milk production and where individuals are predominantly culled in response to health issues. Animals varied in their change in RLTL between subsequent measurements and RLTL shortened more during early life and following hotter summers which are known to cause heat stress in dairy cows. The average amount of telomere attrition calculated over multiple repeat samples of individuals predicted a shorter productive lifespan, suggesting a link between telomere loss and health. TL attrition was a better predictor of when an animal was culled than their average TL or the previously for this population reported significant TL at the age of 1 year. Our present results support the hypothesis that TL is a flexible trait that is affected by environmental factors and that telomere attrition is linked to animal health and survival traits. Change in telomere length may represent a useful biomarker in animal welfare studies.

RevDate: 2021-03-29
CmpDate: 2021-03-12

Feuerbach L (2021)

Formal reply to "Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX".

Nature communications, 12(1):1551.

RevDate: 2021-03-29
CmpDate: 2021-03-12

de Nonneville A, RR Reddel (2021)

Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX.

Nature communications, 12(1):1552.

RevDate: 2021-03-20

Sánchez-Vázquez R, Martínez P, MA Blasco (2021)

AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis.

PLoS genetics, 17(3):e1009410.

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9. We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients or immune regulators, and this has an impact on tumorigenesis potential.

RevDate: 2021-03-10

Yu G, Lu L, Ma Z, et al (2021)

Genetically Predicted Telomere Length and Its Relationship With Alzheimer's Disease.

Frontiers in genetics, 12:595864.

Are shorter telomeres causal risk factors for Alzheimer's disease (AD)? This study aimed to examine if shorter telomeres were causally associated with a higher risk of AD using Mendelian randomization (MR) analysis. Two-sample MR methods were applied to the summary effect sizes and standard errors from a genome-wide association study for AD. Twenty single nucleotide polymorphisms of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and complemented with the other three methods: weighted median approaches, MR-Egger regression, and weighted mode approach. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. We found that longer telomeres were associated with lower risks of AD (odds ratio = 0.79, 95% confidence interval: 0.67, 0.93, P = 0.004). Comparable results were obtained using weighted median approaches, MR-Egger regression, and weighted mode approaches. The intercept of the MR-Egger regression was close to zero. This may show that there was not suggestive of horizontal pleiotropy. Our findings provided additional evidence regarding the putative causal association between shorter telomere length and the higher risk of AD.

RevDate: 2021-04-09

Tarry-Adkins JL, Aiken CE, Dearden L, et al (2021)

Exploring Telomere Dynamics in Aging Male Rat Tissues: Can Tissue-Specific Differences Contribute to Age-Associated Pathologies?.

Gerontology, 67(2):233-242.

INTRODUCTION: Due to increasing lifespan, global aging rates are rising rapidly and age-associated diseases are increasing. To ensure that health span is concomitant with life span, a greater understanding of cellular mechanisms of aging is important.

METHODS: Telomere length analysis from a wide range of tissues from weaning, young adult, and middle-aged (3, 12 and 52 week) male Wistar rats were conducted using Southern blotting. Telomere lengths were compared between tissues and ages using regression models based on the ratios of longest-to-shortest telomere fragments.

RESULTS: Robust linear age-dependent telomere attrition was observed in the liver; 3 versus 12 weeks, 3 versus 52 weeks (p < 0.01), 12 versus 52 weeks (p < 0.05) and the heart; 3 versus 12 weeks (p < 0.05) and 3 versus 52 weeks (p < 0.001). More subtle shortening was observed in aorta and epididymal fat; 3 and 12 versus 52 weeks (p < 0.001) and in skeletal muscle; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). Young thymus telomeres increased in length (3 vs. 12 weeks) and then shortened between 12 and 52 weeks (p < 0.001). We also reported disparity in telomere shortening within tissues: telomeres in aging brain cortex significantly shortened; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). This was not seen in the hypothalamic region. A robust stepwise shortening was observed in the renal cortex; 3 versus 12 weeks, 12 versus 52 weeks (p < 0.05), and 3 versus 52 weeks (p < 0.001), which was not as apparent in the renal medulla; 3 versus 12 weeks (p < 0.01) and 3 versus 52 weeks (p < 0.01). The vastus lateralis skeletal muscle demonstrated the shortest telomere length at weaning and underwent robust age-associated attrition; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). We demonstrated that specific tissues exhibit unique telomere attrition profiles which may partially explain why certain diseases are more prevalent in aged individuals.

DISCUSSION/CONCLUSION: We show wide variations between tissues in vulnerability to the aging process. In the future, this may help target potential interventions to improve health span.

RevDate: 2021-03-17

Mentegari E, Bertoletti F, Kissova M, et al (2021)

A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres.

International journal of molecular sciences, 22(5):.

Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism.

RevDate: 2021-03-10

Aronen T, Virta S, S Varis (2021)

Telomere Length in Norway Spruce during Somatic Embryogenesis and Cryopreservation.

Plants (Basel, Switzerland), 10(2):.

Telomeres i.e., termini of the eukaryotic chromosomes protect chromosomes during DNA replication. Shortening of telomeres, either due to stress or ageing is related to replicative cellular senescence. There is little information on the effect of biotechnological methods, such as tissue culture via somatic embryogenesis (SE) or cryopreservation on plant telomeres, even if these techniques are widely applied. The aim of the present study was to examine telomeres of Norway spruce (Picea abies (L.) Karst.) during SE initiation, proliferation, embryo maturation, and cryopreservation to reveal potential ageing or stress-related effects that could explain variation observed at SE process. Altogether, 33 genotypes from 25 families were studied. SE initiation containing several stress factors cause telomere shortening in Norway spruce. Following initiation, the telomere length of the embryogenic tissues (ETs) and embryos produced remains unchanged up to one year of culture, with remarkable genotypic variation. Being prolonged in vitro culture can, however, shorten the telomeres and should be avoided. This is achieved by successful cryopreservation treatment preserving telomere length. Somatic embryo production capacity of the ETs was observed to vary a lot not only among the genotypes, but also from one timepoint to another. No connection between embryo production and telomere length was found, so this variation remains unexplained.

RevDate: 2021-03-16

Yegorov YE, Poznyak AV, Nikiforov NG, et al (2021)

Role of Telomeres Shortening in Atherogenesis: An Overview.

Cells, 10(2):.

It is known that the shortening of the telomeres leads to cell senescence, accompanied by acquiring of pro-inflammatory phenotype. The expression of telomerase can elongate telomeres and resist the onset of senescence. The initiation of atherosclerosis is believed to be associated with local senescence of the endothelial cells of the arteries in places with either low or multidirectional oscillatory wall shear stress. The process of regeneration of the artery surface that has begun does not lead to success for several reasons. Atherosclerotic plaques are formed, which, when developed, lead to fatal consequences, which are the leading causes of death in the modern world. The pronounced age dependence of the manifestations of atherosclerosis pushes scientists to try to link the development of atherosclerosis with telomere length. The study of the role of telomere shortening in atherosclerosis is mainly limited to measuring the telomeres of blood cells, and only in rare cases (surgery or post-mortem examination) are the telomeres of local cells available for measurement. The review discusses the basic issues of cellular aging and the interpretation of telomere measurement data in atherosclerosis, as well as the prospects for the prevention and possible treatment of atherosclerosis.

RevDate: 2021-03-10

Howard JT, Janak JC, Santos-Lozada AR, et al (2021)

Telomere Shortening and Accelerated Aging in US Military Veterans.

International journal of environmental research and public health, 18(4):.

A growing body of literature on military personnel and veterans' health suggests that prior military service may be associated with exposures that increase the risk of cardiovascular disease (CVD), which may differ by race/ethnicity. This study examined the hypothesis that differential telomere shortening, a measure of cellular aging, by race/ethnicity may explain prior findings of differential CVD risk in racial/ethnic groups with military service. Data from the first two continuous waves of the National Health and Nutrition Examination Survey (NHANES), administered from 1999-2002 were analyzed. Mean telomere length in base pairs was analyzed with multivariable adjusted linear regression with complex sample design, stratified by sex. The unadjusted mean telomere length was 225.8 base shorter for individuals with prior military service. The mean telomere length for men was 47.2 (95% CI: -92.9, -1.5; p < 0.05) base pairs shorter for men with military service after adjustment for demographic, socioeconomic, and behavioral variables, but did not differ significantly in women with and without prior military service. The interaction between military service and race/ethnicity was not significant for men or women. The results suggest that military service may contribute to accelerated aging as a result of health damaging exposures, such as combat, injury, and environmental contaminants, though other unmeasured confounders could also potentially explain the results.

RevDate: 2021-03-10

Lai TP, Simpson M, Patel K, et al (2021)

Telomeres and replicative cellular aging of the human placenta and chorioamniotic membranes.

Scientific reports, 11(1):5115.

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.

RevDate: 2021-03-05

Juríková K, De Wulf P, E Cusanelli (2021)

Nuclear Periphery and Telomere Maintenance: TERRA Joins the Stage.

Trends in genetics : TIG pii:S0168-9525(21)00048-2 [Epub ahead of print].

Long noncoding (lnc)RNAs derived from telomeres, the ends of linear eukaryotic chromosomes, help to maintain telomere length and stability by multiple means, including regulation of telomerase activity and recombination-based telomere maintenance. New findings in yeast promote a model in which telomere attachment to the nuclear envelope regulates telomere transcription and maintenance.

RevDate: 2021-03-16

Pepke ML, DTA Eisenberg (2021)

On the comparative biology of mammalian telomeres: Telomere length co-evolves with body mass, lifespan and cancer risk.

Molecular ecology [Epub ahead of print].

Telomeres, the short repetitive DNA sequences that cap the ends of linear chromosomes, shorten during cell division and are implicated in senescence in most species. Telomerase can rebuild telomeres but is repressed in many mammals that exhibit replicative senescence, presumably as a tumour suppression mechanism. It is therefore important to understand the co-evolution of telomere biology and life-history traits that has shaped the diversity of senescence patterns across species. Gomes et al. previously produced a large data set on telomere length (TL), telomerase activity, body mass and lifespan among 57 mammal species. We re-analysed their data using the same phylogenetic multiple regressions and with several additional analyses to test the robustness of the findings. We found substantial inconsistencies in our results compared to Gomes et al.'s. Consistent with Gomes et al. we found an inverse association between TL and lifespan. Contrary to the analyses in Gomes et al., we found a generally robust inverse association between TL and mass, and only weak nonrobust evidence for an association between telomerase activity and mass. These results suggest that shorter TL may have been selected for in larger and longer lived species, probably as a mechanism to suppress cancer. We support this hypothesis by showing that longer telomeres predict higher cancer risk across 22 species. Furthermore, we find that domesticated species have longer telomeres. Our results call into question past interpretations of the co-evolution of telomere biology and life-history traits and stress the need for careful attention to model construction.

RevDate: 2021-03-05

Katipoglu B, MI Naharci (2021)

Comment on: Non-esterified fatty acids and telomere length in older adults.

Metabolism open, 9:100084.

RevDate: 2021-03-03

Wood EM, Capilla-Lasheras P, Cram DL, et al (2021)

Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.

Molecular ecology [Epub ahead of print].

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their non-breeding subordinates. Here we use extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their non-reproductive subordinates.

RevDate: 2021-03-11

Vangorder-Braid JT, Sirman AE, Kucera AC, et al (2021)

TA-65 does not increase telomere length during post-natal development in house sparrow chicks (Passer domesticus).

Journal of experimental zoology. Part A, Ecological and integrative physiology, 335(3):359-366.

Telomeres, protective caps at the end of chromosomes, are often positively related to lifespan and are thought to be an important mechanism of organismal aging. To better understand the casual relationships between telomere length and longevity, it is essential to be able to experimentally manipulate telomere dynamics (length and loss rate). Previous studies suggest that exposure to TA-65, an extract from the Chinese root Astragalus membranaceus, activates telomerase, lengthens telomeres, increases the growth of keratin-based structures, and boosts the immune system in adults. However, telomere loss is expected to be greatest during early life but whether TA-65 has similar effects during this life stage is currently unknown. Here, we experimentally exposed free-living house sparrow (Passer domesticus) chicks to TA-65 during post-natal development and examined the effects on telomere length and loss, growth of keratin-based structures, and a measure of cellular immunity. Contrary to expectation, the growth of keratin-based structures was reduced in TA-65 chicks and in the second year of the study, chicks exposed to TA-65 experienced more telomere loss than controls. Thus, the effects of TA-65 on telomeres and keratin-based structures differ across life stages and future research will be necessary to determine the mechanisms underlying these age-specific effects.

RevDate: 2021-03-02

Guillén Fajardo R, Otero Fariña F, Mosquera Rey A, et al (2021)

Relationship between the dynamics of telomere loss in peripheral blood leukocytes from osteoarthritis patients and mitochondrial DNA haplogroup.

The Journal of rheumatology pii:jrheum.201316 [Epub ahead of print].

OBJECTIVE: The evaluation of the evolution of telomere length from peripheral blood leukocytes (PBL) in subjects from the Osteoarthritis Initiative (OAI) cohort in relation to the incidence of osteoarthritis (OA) and explore its possible interactive influence with the mitochondrial DNA (mtDNA) haplogroup.

METHODS: Dynamics of telomere sequence loss was quantified in PBL from initially healthy individuals, without symptoms or radiological signs, 78 carrying the mtDNA cluster HV and 47 with cluster JT, from the OAI, during a 72-month follow-up. The incidence of knee OA during this period (n=39) was radiographically established when Kellgren-Lawrence (KL) score increased from < 2 at recruitment to ≥ 2 during 72 months of follow-up. Multivariate analysis using binary logistic regression was performed to assess PBL telomere loss and mtDNA haplogroups as associated risk factors of incidence of knee OA RESULTS: Carriers of cluster HV showed an OA incidence twice that of the JT carriers (n=30 vs. n=9). Rate of PBL telomere loss was higher in cluster HV carriers and in incident individuals. Multivariate analysis showed that the dynamics of PBL telomere shortening can be a consistent risk marker of knee OA incidence. Non-incidents showed a slower telomere loss than incidents, the difference being more significant in carriers of cluster JT than in HV.

CONCLUSION: An increased telomere loss rate in PBL may reflect a systemic accelerated senescence phenotype which could be potentiated by the mitochondrial function, increasing the susceptibility of developing OA.

RevDate: 2021-03-04

Reed J, Kirkman LA, Kafsack BF, et al (2021)

Telomere length dynamics in response to DNA damage in malaria parasites.

iScience, 24(2):102082.

Malaria remains a major cause of morbidity and mortality in the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double-strand breaks within subtelomeric regions. We observed that the process of telomere healing induces the initial synthesis of telomere repeats well in excess of the minimal number required for end stability. However, once stabilized, these newly created telomeres appear to function normally, eventually returning to a length nearing that of intact chromosome ends. These results parallel recent observations in humans, suggesting an evolutionarily conserved mechanism for chromosome end repair.

RevDate: 2021-04-02

Kockler ZW, Comeron JM, A Malkova (2021)

A unified alternative telomere-lengthening pathway in yeast survivor cells.

Molecular cell pii:S1097-2765(21)00090-3 [Epub ahead of print].

Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.

RevDate: 2021-02-28

Sullivan DI, Jiang M, Hinchie AM, et al (2021)

Transcriptional and Proteomic Characterization of Telomere-Induced Senescence in a Human Alveolar Epithelial Cell Line.

Frontiers in medicine, 8:600626.

Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.

RevDate: 2021-02-26

Lin Z, Gao H, Wang B, et al (2021)

Cytomegalovirus Infection and Its Relationship with Leukocyte Telomere Length: A Cross-Sectional Study.

Mediators of inflammation, 2021:6675353.

Background: Telomeres undergo shortening with each cell division, which could be accelerated by infection. The association between virus infection and telomere length is poorly understood. In the present study, we investigated the putative associations between leukocyte telomere length (TL), cytomegalovirus (CMV) infection, and C-reactive protein (CRP) in a national representative sample of noninstitutionalized population.

Methods: We analyzed data that was collected in a cross-sectional setting, where 3,987 participants were enrolled with available data on telomere length. The association between telomere length with previous CMV infection and CRP was analyzed using multivariable linear regression models. We further tested if obesity, measured by body mass index (BMI), and smoking could modify this relationship.

Results: In total, around 46% percent of the study population were men and 54% were women. Average ages were 35.1 years for men and 35.0 years for women. One unit increase of CMV antibody IgG titer was associated with -0.07 (95% confidence interval: -0.12, -0.01) unit decrease of leukocyte TL when sex was adjusted for. After additionally adjusting for BMI and smoking status, the magnitude of the association was only slightly decreased to -0.06 (95% confidence interval: -0.11, -0.01). The effect sizes were comparable after additionally adjusting for CRP. These analyses imply that previous CMV infection affects leukocyte TL through pathways other than CRP.

Conclusions: Previous CMV infection was associated with shorter leukocyte TL. This association was independent of CRP.

RevDate: 2021-03-12
CmpDate: 2021-03-03

Hartlieb SA, Sieverling L, Nadler-Holly M, et al (2021)

Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome.

Nature communications, 12(1):1269.

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.

RevDate: 2021-03-19

Li X, Zhang J, Yang Y, et al (2021)

MicroRNA-340-5p increases telomere length by targeting telomere protein POT1 to improve Alzheimer's disease in mice.

Cell biology international [Epub ahead of print].

Alzheimer's disease (AD) is a chronic neurodegenerative disorder which is the primary cause of dementia in the elderly. Telomere attrition has been proposed as a hallmark of aging. Our study aimed to explore the mechanism of the protection of telomere 1 (POT1) in regulating telomere length and affecting cellular senescence in AD. The AD mouse model was established by d-galactose and aluminum chloride, and the water maze test and dark avoidance test were used to detect the behaviors of mice and confirm the success of AD mouse model. AD cell model was established with HT22 cells induced by Aβ42 oligomers. POT1 expression in the AD model was detected by quantitative real-time polymerase chain reaction. Cellular telomere length in hippocampal tissue was analyzed by telomere restriction fragment. Localization of intracellular POT1, telomerase, and telomeres was analyzed by immunofluorescence and fluorescence in situ hybridization. Dual-luciferase assay was used to validate the targeted binding relationship between microRNA-340-5p (miR-340-5p) and POT1. After inhibiting POT1 expression, the symptoms of AD in mice were improved. Aβ1-42 deposition was reduced, whereas telomere length and telomerase activity was increased. Dual-luciferase assay verified the binding relationship between miR-340-5p and POT1. An increase in miR-340-5p expression could alleviate cellular senescence and AD symptoms. miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms. This study made a conclusion that miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms in mice.

RevDate: 2021-02-24

Banach M, PE Penson (2020)

Cellular senescence, telomeres, and cardiovascular risk in familial hypercholesterolaemia.

European journal of preventive cardiology pii:6055398 [Epub ahead of print].

RevDate: 2021-02-24

Baragetti A, Bonacina F, Da Dalt L, et al (2020)

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors.

European journal of preventive cardiology pii:5983847 [Epub ahead of print].

AIMS: Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects.

METHODS AND RESULTS: LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls.

CONCLUSIONS: We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

RevDate: 2021-02-24

Michels N, van Aart CJC, Martens DS, et al (2020)

Telomere length and cardiovascular disease precursors: a 7-year follow-up from childhood to early adolescence.

European journal of preventive cardiology pii:5999091 [Epub ahead of print].

RevDate: 2021-04-09

Mehta SR, Iudicello JE, Lin J, et al (2021)

Telomere length is associated with HIV infection, methamphetamine use, inflammation, and comorbid disease risk.

Drug and alcohol dependence, 221:108639.

BACKGROUND: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers.

METHODS: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF).

RESULTS: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003).

CONCLUSIONS: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health.

RevDate: 2021-03-16

Poláková E, Záhonová K, Albanaz ATS, et al (2021)

Diverse telomeres in trypanosomatids.

Parasitology pii:S0031182021000378 [Epub ahead of print].

Telomeres are the ends of linear eukaryotic chromosomes facilitating the resolution of the ‘end replication and protection’ problems, associated with linearity. At the nucleotide level, telomeres typically represent stretches of tandemly arranged telomeric repeats, which vary in length and sequence among different groups of organisms. Recently, a composition of the telomere-associated protein complex has been scrutinized in Trypanosoma brucei. In this work, we subjected proteins from that list to a more detailed bioinformatic analysis and delineated a core set of 20 conserved proteins putatively associated with telomeres in trypanosomatids. Out of these, two proteins (Ku70 and Ku80) are conspicuously missing in representatives of the genus Blastocrithidia, yet telomeres in these species do not appear to be affected. In this work, based on the analysis of a large set of trypanosomatids widely different in their phylogenetic position and life strategies, we demonstrated that telomeres of trypanosomatids are diverse in length, even within groups of closely related species. Our analysis showed that the expression of two proteins predicted to be associated with telomeres (those encoding telomerase and telomere-associated hypothetical protein orthologous to Tb927.6.4330) may directly affect and account for the differences in telomere length within the species of the Leishmania mexicana complex.

RevDate: 2021-03-17
CmpDate: 2021-03-17

Bi J, Wu M, Liu Y, et al (2021)

Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study.

Ecotoxicology and environmental safety, 213:112037.

OBJECTIVE: Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life. Newborn TL is sensitive to maternal metals concentrations, while study about the association between maternal manganese (Mn) concentrations and newborn TL was not found. Our study aimed to investigate whether newborn TL is related to maternal Mn concentrations.

METHODS: Data were collected from a birth cohort study of 762 mother-newborn pairs conducted from November 2013 to March 2015 in Wuhan, China. We measured the Mn concentrations in spot urine samples collected during three trimesters by inductively coupled plasma mass spectrometry (ICP-MS) and relative cord blood TL by quantitative real-time polymerase chain reaction (qPCR). We applied multiple informant models to investigate the associations between maternal Mn concentrations and cord blood TL.

RESULTS: The geometric mean of creatinine-corrected urinary Mn concentrations were 1.58 μg/g creatinine, 2.53 μg/g creatinine, and 2.62 μg/g creatinine in the first, second, and third trimester, respectively. After adjusting for potential confounders, a doubling of maternal urinary Mn concentration during the second trimester was related to a 2.10% (95% CI: 0.25%, 3.99%) increase in cord blood TL. Mothers with the highest tertile of urinary Mn concentrations during the second trimester had a 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL than those with the lowest tertile. This association was more evident in male infants. No relationship was found between maternal urinary Mn concentrations and cord blood TL during the first and third trimesters in our study.

CONCLUSIONS: Our findings suggested that maternal Mn concentration during the second trimester was positively associated with newborn TL. These results might provide an epidemiology evidence on the protective role of maternal Mn for newborn TL and offer clues for the early prevention of telomere shortening related diseases.

RevDate: 2021-03-26

Lim CJ, TR Cech (2021)

Publisher Correction: Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.

Nature reviews. Molecular cell biology, 22(4):299.

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