Age-related telomere attrition causes aberrant gene expression in sub-telomeric regions.
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ABSTRACT:
SUBMITTER: Dong X
PROVIDER: S-EPMC8208793 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.
| S-EPMC10352551 | biostudies-literature
Project description:We have reported telomere attrition in β and α cells of the pancreas in elderly patients with type 2 diabetes, but it has not been explored how the telomere lengths of these islet cells change according to age in normal subjects. To examine the telomere lengths of β and α cells in individuals without diabetes across a wide range of ages, we conducted measurement of the telomere lengths of human pancreatic β and α cells obtained from 104 autopsied subjects without diabetes ranging in age from 0 to 100 years. As an index of telomere lengths, the normalized telomere-centromere ratio (NTCR) was determined for β (NTCRβ) and α (NTCRα) cells by quantitative fluorescence in situ hybridization (Q-FISH). We found NTCRβ and NTCRα showed almost the same levels and both decreased according to age (p < 0.001 for both). NTCRs decreased more rapidly with age and were more widely distributed (p = 0.036 for NTCRβ, p < 0.001 for NTCRα) in subjects under 18 years of age than in subjects over 18 years. There was a positive correlation between NTCRβ and NTCRα only among adult subjects (p < 0.001). In conclusion, the telomeres of β and α cells become shortened with normal aging process.
| S-EPMC5005922 | biostudies-literature
Project description:Telomere shortening with age has been documented in many organisms, but few studies have reported telomere length measurements in amphibians, and no information is available for growth after metamorphosis, nor in wild populations. We provide both cross-sectional and longitudinal evidence of net telomere attrition with age in a wild amphibian population of natterjack toads (Epidalea calamita). Based on age-estimation by skeletochronology and qPCR telomere length measurements in the framework of an individual-based monitoring programme, we confirmed telomere attrition in recaptured males. Our results support that toads experience telomere attrition throughout their ontogeny, and that most attrition occurs during the first 1-2 years. We did not find associations between telomere length and inbreeding or body condition. Our results on telomere length dynamics under natural conditions confirm telomere shortening with age in amphibians and provide quantification of wide telomere length variation within and among age-classes in a wild breeding population.
| S-EPMC7423040 | biostudies-literature
Project description:Genome dynamics was investigated within natural populations of the soil bacterium Streptomyces. The exploration of a set of closely related strains isolated from micro-habitats of a forest soil exhibited a strong diversity of the terminal structures of the linear chromosome, i.e. terminal inverted repeats (TIRs). Large insertions, deletions and translocations could be observed along with evidence of transfer events between strains. In addition, the telomere and its cognate terminal protein complexes required for terminal replication and chromosome maintenance, were shown to be variable within the population probably reflecting telomere exchanges between the chromosome and other linear replicons (i.e., plasmids). Considering the close genetic relatedness of the strains, these data suggest that the terminal regions are prone to a high turnover due to a high recombination associated with extensive horizontal gene transfer.
| S-EPMC7205883 | biostudies-literature
Project description:Telomere attrition is increased in various disorders and is therefore a potential biomarker for diagnosis and/or prognosis of these disorders. The contribution of telomere attrition in the pathogenesis of neurodegenerative disorders is yet to be fully elucidated. We are reviewing the current knowledge regarding the telomere biology in two common neurodegenerative disorders, Alzheimer's disease (AD), and Parkinson's disease (PD). Furthermore, we are discussing future prospective of telomere research in these disorders. The majority of studies reported consistent evidence of the accelerated telomere attrition in AD patients, possibly in association with elevated oxidative stress levels. On the other hand in PD, various studies reported contradictory evidence regarding telomere attrition. Consequently, due to the low specificity and sensitivity, the clinical benefit of telomere length as a biomarker of neurodegenerative disease development and progression is not yet recognized. Nevertheless, longitudinal studies in large carefully selected cohorts might provide further elucidation of the complex involvement of the telomeres in the pathogenesis of neurodegenerative diseases. Telomere length maintenance is a complex process characterized by environmental, genetic, and epigenetic determinants. Thus, in addition to the selection of the study cohort, also the selection of analytical methods and types of biological samples for evaluation of the telomere attrition is of utmost importance.
| S-EPMC7373805 | biostudies-literature
Project description:The molecular mechanisms that drive hematopoietic stem cell (HSC) functional decline under conditions of stress are not completely understood. Here, in light of the recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells (HSCs) under telomeric stress, as that induced by pathogenic germline mutations in telomerase complex genes. These analyses revealed that telomere attrition maintains HSCs in a state of persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of interferon (IFN) signaling response, which directly comprises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Telomerase reactivation completely restored HSC transcriptional homeostasis at the single-cell level, overcame enhanced megakaryocytic differentiation and significantly ameliorated HSCs’ repopulation capacity in the setting of competitive transplantation, suggesting that HSCs can repristinate their function upon telomere damage resolution. This study challenges the long-standing hypothesis that telomere attrition limits the proliferative potential of HSCs by inducing apoptosis or senescence and suggests that early intervention targeting the IFN axis could prevent bone marrow failure syndromes in patients with pathogenic mutations affecting telomere maintenance.
2021-10-23 | GSE169709 | GEO
Project description:Here we found that ILF3 prefers to bind telomere R-loops and protects telomere from aberrant homologous recombination. ILF3 knockout induces TERRA aggregation onto telomere and activates telomere DNA damage response (DDR). Furthermore, ILF3 deficiency disrupts telomere homeostasis and induces abnormal ALT-mediated telomere lengthening
2022-03-04 | PXD032093 |
Project description:BACKGROUND:DNA packaging into chromatin regulates all DNA-related processes and at chromosomal ends could affect both essential functions of telomeres: protection against DNA damage response and telomere replication. Despite this primordial role of chromatin, little is known about chromatin organization, and in particular about nucleosome positioning on unmodified subtelomere-telomere junctions in Saccharomyces cerevisiae. RESULTS:By ChEC experiments and indirect end-labeling, we characterized nucleosome positioning as well as specialized protein-DNA associations on most subtelomere-telomere junctions present in budding yeast. The results show that there is a relatively large nucleosome-free region at chromosome ends. Despite the absence of sequence homologies between the two major classes of subtelomere-telomere junctions (i.e.: Y'-telomeres and X-telomeres), all analyzed subtelomere-telomere junctions show a terminal nucleosome-free region just distally from the known Rap1-covered telomeric repeats. Moreover, previous evidence suggested a telomeric chromatin fold-back structure onto subtelomeric areas that supposedly was implicated in chromosome end protection. The in vivo ChEC method used herein in conjunction with several proteins in a natural context revealed no evidence for such structures in bulk chromatin. CONCLUSIONS:Our study allows a structural definition of the chromatin found at chromosome ends in budding yeast. This definition, derived with direct in vivo approaches, includes a terminal area that is free of nucleosomes, certain positioned nucleosomes and conserved DNA-bound protein complexes. This organization of subtelomeric and telomeric areas however does not include a telomeric cis-loopback conformation. We propose that the observations on such fold-back structures may report rare and/or transient associations and not stable or constitutive structures.
| S-EPMC7243337 | biostudies-literature
Project description:Longitudinal studies have sought to establish whether environmental exposures such as smoking accelerate the attrition of individuals' telomeres over time. These studies typically control for baseline telomere length (TL) by including it as a covariate in statistical models. However, baseline TL also differs between smokers and non-smokers, and telomere attrition is spuriously linked to baseline TL via measurement error and regression to the mean. Using simulated datasets, we show that controlling for baseline TL overestimates the true effect of smoking on telomere attrition. This bias increases with increasing telomere measurement error and increasing difference in baseline TL between smokers and non-smokers. Using a meta-analysis of longitudinal datasets, we show that as predicted, the estimated difference in telomere attrition between smokers and non-smokers is greater when statistical models control for baseline TL than when they do not, and the size of the discrepancy is positively correlated with measurement error. The bias we describe is not specific to smoking and also applies to other exposures. We conclude that to avoid invalid inference, models of telomere attrition should not control for baseline TL by including it as a covariate. Many claims of accelerated telomere attrition in individuals exposed to adversity need to be re-assessed.
| S-EPMC6837209 | biostudies-literature
Project description:Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND - Quantitative Telomeric chromatin Isolation Protocol followed by isolation of Proteins On Nascent DNA - which enables purification of proteins that associate with telomeres specifically during replication. In addition to the core replisome, we identify a large number of proteins that specifically associate with telomere replication forks. Depletion of several of these proteins induces telomere fragility validating their importance for telomere replication. We also find that at telomere replication forks the single strand telomere binding protein POT1 is depleted, whereas histone H1 is enriched. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.
| S-EPMC8643687 | biostudies-literature