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Investigating the role of telomere length in 3D spatiotemporal gene regulation in cardiomyocytes [RNA-Seq]

ABSTRACT: Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in ageing and are targets of DNA damage and DNA damage response. Although short telomeres have been implicated in heart failure, little is known about the role of telomeres in cardiomyocytes.To fill this gap in knowledge, we studied myocardial ageing in the form of telomere lengths under isogenic background.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217701 | GEO | 2023/12/31

REPOSITORIES: GEO

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Investigating the role of telomere length in 3D spatiotemporal gene regulation in cardiomyocytes [CUT&Tag]

Project description:Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in ageing and are targets of DNA damage and DNA damage response. Although short telomeres have been implicated in heart failure, little is known about the role of telomeres in cardiomyocytes.To fill this gap in knowledge, we studied myocardial ageing in the form of telomere lengths under isogenic background.

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Investigating the role of telomere length in 3D spatiotemporal gene regulation in cardiomyocytes [Hi-C]

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Endogenous genes regulated by telomere length

Project description:Reporter genes inserted immediately adjacent to telomeres are frequently repressed in cells of model organisms as well as human cells, a phenomena referred to as telomere position effect (TPE). TPE has been proposed to be involved in regulation of cellular senescence, cancer and aging. However, the identification of endogenous genes in human cells regulated by natural telomeres has not been reported. Here we show that the expression of interferon simulated gene 15 (ISG15, located on 1p36.33, G1P2) varies with telomere length. ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases with the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The up-regulation of ISG15 is independent of p53 and type I interferon, and is not due to replicative senescence and DNA damage. In human skin specimens obtained from various aged individuals, ISG15 was up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and it suggests that telomeres may be involved in the regulation of human physiology that contributes to the process of aging. Keywords: cell type comparison

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Telomere length effect on genes near the telomere in myoblasts

Project description:We examined differential expression of genes within 10MBs of telomeres in myoblasts with long or short telomeres We offer telomere looping with telomere length as a partial mechanistic explanation for the changes gene expression that is observed. Compare expression of genes within 10MB of the telomere in normal myoblasts with long (15 kb) and short (6 kb) telomeres.

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Telomere length effect on genes near the telomere in myoblasts

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Investigating the role of telomere length in 3D spatiotemporal gene regulation in cardiomyocytes

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-31 | GSE217703 | GEO

ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

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Dynamics of Telomere Rejuvenation During Chemical Induction to Pluripotent Stem Cells

Project description:Chemical induced pluripotent stem cells (CiPSCs) have been successfully achieved and may provide an alternative and attractive source for stem cell-based therapy. Sufficient telomere lengths are critical for unlimited self-renewal and genomic stability of pluripotent stem cells. Dynamics of telomere reprogramming and whether and how telomeres are sufficiently elongated in the CiPSCs have remained to be understood. We show that CiPSCs acquire telomere lengthening with increasing passages after clonal formation. Both telomerase activity and recombination-based mechanisms are involved in the telomere elongation. Telomere lengths strongly indicate the degree of reprogramming, pluripotency and differentiation capacity of CiPSCs. Nevertheless, telomere damage and shortening occur at late stage of lengthy induction, limiting CiPSC formation. Recombination mechanism is not activated during induction until CiPSC clonal formation and passages. We find that histone crotonylation induced by crotonic acid can activate two-cell genes including Zscan4, alleviate telomere damage and shortening during induction and promote CiPSC generation. Moreover, crotonylation decreases abundance of heterochromatic H3K9me3 and HP1a at subtelomeres and Zscan4 loci. Taken together, telomere rejuvenation links to reprogramming and pluripotency of CiPSCs. Crotonylation facilitates telomere maintenance and enhances chemical induced reprogramming to pluripotency.

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Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage

Project description:Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. -H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.

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