Senescence‐associated transcriptional derepression in subtelomeres is determined in a chromosome‐end‐specific manner

Abstract

Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation. Indeed, the subtelomeres containing these derepressed genes are enriched in factors of polycomb repression (EZH2 and H3K27me3), insulation (CTCF and MAZ), and cohesion (RAD21 and SMC3) while being associated with the open A‐type chromatin compartment. These findings unveil that the subtelomere transcriptome associated with senescence is determined in a chromosome‐end‐specific manner according to the type of higher‐order chromatin structure.

Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review

“…Consequently, lamins, which are nuclear envelope proteins that interact with laminin, are involved in cellular senescence. Lamin B1, a nuclear layer factor down-regulated in senescent cells, is involved in the regulation of subtelomere genes [ 82 ]. The knockdown of METTL14 reduced the m 6 A level of the lamin B receptor, leading to instability of the lamin B receptor mRNA, which in turn leads to cellular senescence [ 83 ].…”