Age‐related telomere attrition causes aberrant gene expression in sub‐telomeric regions

Abstract

Telomere attrition has been proposed as a biomarker and causal factor in aging. In addition to causing cellular senescence and apoptosis, telomere shortening has been found to affect gene expression in subtelomeric regions. Here, we analyzed the distribution of age‐related differentially expressed genes from the GTEx RNA sequencing database of 54 tissue types from 979 human subjects and found significantly more upregulated than downregulated genes in subtelomeric regions as compared to the genome‐wide average. Our data demonstrate spatial relationships between telomeres and gene expression in aging.

Telomere Position Effect Over Long Distance acts as a genome-wide epigenetic regulator through a commoncis- element

“…One could hypothesize, that the combination of telomere length heterogeneity coupled with WE-polymorphisms (Alu Y -like repeats) offers an endless combination of systems where TPE-OLD associated genes are affected upon stimuli either by telomere shortening (progressive) or WE-polymorphisms (static). This new context could explain the enrichment of deregulation reported by others at subtelomeres 31 . In large panels, chances are that telomere shortening and WE-polymorphisms allowing genes to be freed from TPE-OLD are more consistently frequent at these specific loci.…”

“…If TPE is restricted to a distance of a few kilobases (kb) from telomeres, the princeps description of TPE-OLD identified genes within 10 Megabases (Mb) from telomeres whose expression is directly impacted by telomere length, without any restrictions towards modulated expression (either up or down) by opposition to the repressive mechanism of TPE. Despite its identification and recent studies suggesting the genome-wide influence of telomere [29][30][31][32] , TPE-OLD features remain only partly characterized.…”

ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first‐degree relatives of type 2 diabetics

“…Increased senescent cell burden in SAT contributes to the development of T2D in elderly (Spinelli et al, 2020). Accordingly, we have investigated whether, in vivo , the upregulation of ZMAT3 transcription, previously identified as a major age‐related gene in most tissues including SAT (Dong et al, 2021), associates with human aging and T2D. To this end, we measured mRNA levels of ZMAT3 in subcutaneous adipose cells from individuals aged 26 to 67.…”

“…In a recent analysis of 17,382 whole transcriptome profiles in 54 tissue types from 979 human donors aged 20 to 79 and included in the GTEx database (V.8), ZMAT3 emerged as one of the top ten age‐related and differentially expressed genes. Importantly, ZMAT3 also showed a significant positive association with age in multiple tissues, including SAT (Dong et al, 2021). In addition, ZMAT3 hypomethylation has been found in the cerebellum of subjects with Down Syndrome, which has been described as a human condition of accelerated aging (Gensous et al, 2019; Mendioroz et al, 2016).…”

Sex‐specific aging in animals: Perspective and future directions

“…Telomere attrition: Telomere attrition in humans correlates with age, and telomere attrition is directly related to cellular senescence (a primary cause of inflammation) and altered gene expression in sub-telomeric regions (Dong et al, 2021). In mammals, the level of telomere maintenance with age depends on body size, with telomerase activity negatively correlated with body mass (Tian et al, 2018).…”