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The role of short telomeres in CD8 TEMRA cells (CCR7- CD45RA+) immune aging: A gene expression microarray study

ABSTRACT: Telomere shortening is universally acquired with aging in humans, but the contribution of telomere shortening to immune aging is not fully understood. Here, we studied T cells derived from short telomere syndrome patients and compared their T cell profile and function to controls and elderly individuals who had normal age-adjusted telomere length. The short telomere syndrome patients were all under age 40 and carried mutant telomerase or telomere genes and had telomere lengths below the 1st age-adjusted percentile. The T cell profile of young short telomere syndrome patients resembled those that were five decades older including a depletion of naive T cell population and accumulation of terminally differentiated effector cells. To test whether short telomeres affect the quality of these cells, we performed a gene expression microarray. The data are summarized here. We found that although numerically expanded in both short telomere and elderly cases, the gene expression microarrays were distinct with short telomere cells predominately upregulating gene expression of DNA damage pathways and elderly T cells upregulating cell extrinsic apoptotic pathways. The goal of the experiment is to highlight important genes and pathways that may drive immune aging in short telomere syndromes and which may also contribute to normal immune aging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77525 | GEO | 2018/09/14

REPOSITORIES: GEO

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Reprogramming of ovarian aging epigenome by resveratrol [RNA-seq]

Project description:Depletion of oocytes and follicles and reduced oocyte quality contribute to age-associated ovarian senescence and infertility. Telomere shortening and altered methylation make two major contributions to general aging. Resveratrol acts as anti-oxidant and Sirt1 activator to alleviate aging including reproductive aging. It remains elusive whether resveratrol can reprogram the aging epigenome. We sought to examine aging ovarian epigenome and the potential effects of resveratrol by combined analysis of telomere length, transcriptome and methylome mainly in oocytes and also in granulosa cells, two major cell types in the ovary.

2021-09-26 | GSE184635 | GEO

Reprogramming of ovarian aging epigenome by resveratrol [methylation]

2021-09-26 | GSE184636 | GEO

Telomere shortening in hiPSCs results in neuronal and astrocyte aging

Project description:Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining telomere length, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of accelerating aging in vitro using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate TERT loss-of-function hiPSCs, resulting in a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes in CNS cell types.

2023-12-09 | GSE240447 | GEO

The Human Telomeric Proteome During Telomere Replication

Project description:Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. In addition, recent evidence revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate through the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we developed QTIP-iPOND, which enables purification of the proteins that associate with telomeres during their replication. We identify in addition to the core replisome a large number of proteins that specifically associate with telomere replication forks and validate their importance.

2021-11-03 | PXD018712 | Pride

Npl3 stabilizes R-loops at telomeres to prevent accelerated replicative senescence

Project description:Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to identify telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple RNA biogenesis processes. Using Chromatin- and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates to telomeres in an R-loop dependent manner, as changes in R-loop levels, e.g. at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches we demonstrate that Npl3 binds to TERRA and stabilizes R-loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.

2020-01-31 | PXD016772 | Pride

DNA methylation - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

Project description:Dyskeratosis congenita (DKC) and idiopathic aplastic anemia (AA) are bone marrow failure syndromes that share characteristics of premature aging with severe telomere attrition. In this study, we analyzed blood samples of 62 AA and 13 DKC patients to demonstrate that their epigenetic age predictions are overall increased, albeit not directly correlated with telomere length. Aberrant DNA methylation was observed in the gene PRDM8 in DKC and AA as well as in other diseases with premature aging phenotype, such as Down syndrome, Werner syndrome and Hutchinson-Gilford-Progeria syndrome. To gain further insight into the functional relevance of PRDM8 we generated induced pluripotent stem cells (iPSCs) with heterozygous and homozygous knockout. Loss of PRDM8 impaired hematopoietic and neuronal differentiation of iPSCs, but it did not impact on epigenetic age. Taken together, aberrant DNA methylation in PRDM8 provides a biomarker for bone marrow failure syndromes, which may contribute to the hematopoietic and neuronal phenotypes of premature aging syndromes.

2020-08-31 | GSE141106 | GEO

Gene expression - PRDM8 reveals aberrant DNA methylation in aging syndromes and is relevant for hematopoietic and neuronal differentiation.

2020-08-31 | GSE141107 | GEO

A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere protection

Project description:RAP1 is one of the components of mammalian shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere protection has remained elusive. RAP1 binds along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres and its deficiency causes a premature aging in mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact in mouse survival, mice lacking both RAP1 and telomerase show a progressive decreased survival with increasing mouse generation as compared to telomerase single mutants. Telomere shortening was more pronounced in Rap1-/- Terc-/- than in Terc-/- counterparts, leading to an earlier onset of DNA damage and its consequent DNA damage response as well as accelerated degenerative pathologies in the intestines. In its turn, telomerase deficiency abolishes RAP1-mediated obesity and liver pathologies. Mouse embryonic fibroblasts with shorten telomeres present less amount of telomere-bound RAP1 but in contrast show higher numbers of RAP1 bound extratelomeric sites genomewide. Absence of RAP1 leads to deregulation of several metabolic pathways, and these changes were more pronounce in cells with short telomeres suggesting that RAP1 release from telomere foci could constitute a coordinated genomic response to telomere shortening. Our findings also demonstrate that although RAP1 is not a key factor in telomere capping under normal conditios, under stress situation such as critical telomere shortening RAP1 exerts an important function for telomere protection and justify its evolutionary conservation as a shelterin component in mammalian cells.

2016-11-16 | GSE79996 | GEO

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Project description:Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, the telomere integrity is not only determined by telomere length but also by epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between telomere shortening-induced DDR and epigenetic modification in aging is unknown. Here we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs), and prolongs lifespan of late generation of telomerase deficient mice (G3Terc-/-). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin status for DDR signaling transduction through the demethylating of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a restores the heterochromatin compaction in the sub-telomeric regions and thereby ameliorating the DDR initiation at short telomeres of G3Terc-/- ISCs. Treatment with a small molecule inhibitor of BER alleviates DDR and improves the maintenance and function of G3Terc-/- ISCs. Taken together, our study discloses a potential therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modulating molecules.

2018-08-22 | GSE117845 | GEO

Telomere shortening is associated with over-expression of subtelomeric genesin thyroid tumors.

Project description:To determine whether telomere shortening in thyroid tumors delineates gene expression of subtelomeric regions, we performed RNA sequencing in a set of tumors (n = 15) and compare gene expression profiles of subtelomeric and non-subtelomeric genes between short telomere tumors and normal telomere tumors. We defined as subtelomeric genes, those located within the 5 megabase windows (Mb) adjacent to the telomeres.

2022-08-24 | GSE193623 | GEO

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