The Chromatin Landscape of Cellular Senescence

Abstract

Cellular senescence, an irreversible growth arrest triggered by a variety of stressors, plays important roles in normal physiology and tumor suppression, but accumulation of senescent cells with age contributes to the functional decline of tissues. Senescent cells undergo dramatic alterations to their chromatin landscape that affect genome accessibility and their transcriptional program. These include the loss of DNA-nuclear lamina interactions, the distension of centromeres, and changes in chromatin composition that can lead to the activation of retrotransposons. Here we discuss these findings, as well as recent advances in microscopy and genomics that have revealed the importance of the higher-order spatial organization of the genome in defining and maintaining the senescent state.

Nuclear Dynamics of Heterochromatin Repair

“…Dramatic changes in heterochromatin structure and organization are also typically observed during aging (reviewed in [104, 105]). Pericentromeric heterochromatin loses both H3K9me3 and HP1 proteins in older flies and human cells, leading to the abnormal expression of satellite sequences [106–108].…”

“…Pericentromeric heterochromatin loses both H3K9me3 and HP1 proteins in older flies and human cells, leading to the abnormal expression of satellite sequences [106–108]. This is potentially linked to an overall reduction of silencing components in older cells and/or their sequestration in genomic region that acquire heterochromatin-like structure, such as the senescence-associated heterochromatin foci (SAHF) observed in human cell cultures [105, 109]. Loss of pericentric heterochromatin silencing is potentially a driving force for age-dependent genome instability and cell lethality.…”

Forces driving the three‐dimensional folding of eukaryotic genomes

“…On the basis of this new knowledge, whole‐genome conformation studies have been used to decipher how development or developmental disease (Dixon et al , ; Fraser et al , ; Lupiáñez et al , ; Franke et al , ; Bonev et al , ), cancer (Flavahan et al , ; Taberlay et al , ; Hnisz et al , ; Wu et al , ), DNA damage (Aymard et al , ; Canela et al , ), cellular aging (Criscione et al , ), and genetic variation (Javierre et al , ) impact on the structure and function of the genome. Needless to say that the advent of 3C technology (see overview in Denker & de Laat, ) has also provided insights into the higher order genomic organization of bacteria (e.g., Le & Laub, ; Lioy et al , ), fungi (e.g., Mizuguchi et al , ; Kim et al , ; Tanizawa et al , ), nematodes (e.g., Crane et al , ), the Plasmodium falciparum parasite (Ay et al , ), and plants (e.g., Dong et al , ).…”

Early Polycomb-target deregulations in Hutchinson-Gilford Progeria Syndrome revealed by heterochromatin analysis

“…Important heterochromatin organizing regions include LADs, along with pericentromeric and telomeric regions, which are crucial for preserving chromosome structure 3,4,10 . Alterations in heterochromatin are associated with developmental defects and cancer, while its proper conformation is a hallmark of healthy cells 52,53 . As such, reliable methods to characterize heterochromatin and its alterations are a crucial need for the biomedical scientific community.…”