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Molecular basis of TPE-OLD [methylation]

ABSTRACT: Among epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomeric-dependent long-distance loops, with a reach of 10Mb from the telomeres. However, TPE-OLD remain poorly defined. We used cells with controlled telomere length combined to a genome wide approach revealing its transcriptome and methylome. We identified a common cis element that behaved as an insulator/ enhancer. By using reporter assays integrating this element, we disclosed additional trans partners further validated by in silico data. Exploiting our cellular model we observed the depletion of one candidate (RBPJ) at TPE-OLD associated loci concomitant to telomere shortening. Therefore, we conclude that TPE-OLD is orchestrated by Alu-like elements acting as enhancers in association with RBPJ. We propose that TPE-OLD functions by the coordinated action of newly evolved enhancers; an associated protein RBPJ and telomere length to produce an adapted response to external stimuli (i.e., Aging)

ORGANISM(S): Homo sapiens

PROVIDER: GSE213427 | GEO | 2023/01/05

REPOSITORIES: GEO

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Molecular basis of TPE-OLD [RNA-seq]

Project description:Among epigenetic modifiers, telomeres, represent attractive modulators of the genome in part through position effects. Telomere Position Effect – Over Long Distances (TPE-OLD) modulates genes expression by changes in telomeric-dependent long-distance loops, with a reach of 10Mb from the telomeres. However, TPE-OLD remain poorly defined. We used cells with controlled telomere length combined to a genome wide approach revealing its transcriptome and methylome. We identified a common cis element that behaved as an insulator/ enhancer. By using reporter assays integrating this element, we disclosed additional trans partners further validated by in silico data. Exploiting our cellular model we observed the depletion of one candidate (RBPJ) at TPE-OLD associated loci concomitant to telomere shortening. Therefore, we conclude that TPE-OLD is orchestrated by Alu-like elements acting as enhancers in association with RBPJ. We propose that TPE-OLD functions by the coordinated action of newly evolved enhancers; an associated protein RBPJ and telomere length to produce an adapted response to external stimuli (i.e., Aging)

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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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