Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts

Abstract

The three-dimensional configuration of the chromatin architecture is known to be crucial for alterations in the transcriptional network; however, the underlying mechanisms of epigenetic control of senescence-related gene expression by modulating the chromatin architecture remain unknown. Here, we demonstrate frequent chromosomal compartment switching during mouse embryonic fibroblasts (MEFs) replicative senescence as characterized by senescence-inactivated (SIAEs) and -activated enhancers (SAEs) in topologically associated domains (TADs). Mechanistically, SAEs are closely correlated with senescence-associated secretory phenotype (SASP) genes, which are a key transcriptional feature of an aging microenvironment that contributes to tumor progression, aging acceleration, and immunoinflammatory responses. Moreover, SAEs can positively regulate robust changes in SASP expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is capable of enhancing SAE activity, which accelerates the emergence of SAEs flanking SASPs and the secretion of downstream factors, contributing to the progression of senescence. Our results provide novel insight into the TAD-related control of SASP gene expression by revealing hierarchical roles of the chromatin architecture, transcription factors, and enhancer activity in the regulation of cellular senescence.

Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

“…In primary fibroblasts, replicative and oncogene-induced senescence is characterized by changes in chromatin organization, including both the formation of senescence-associated heterochromatin foci (SAHF) as well as regions of enhancer activation, leading to alterations in gene transcription [52][53][54][55]. We recently reported that CDK4/6 inhibitors can induce similar changes in luminal breast cancer cells, both in vitro and in vivo (including in clinical specimens).…”

ATF3 drives senescence by reconstructing accessible chromatin profiles

“…DNA methylation alterations and histone modifications change chromatin architecture in ways that affect gene expression profiles and thus determine cell fate. Previous researches showed that structural changes in chromatin are closely connected to senescence (Guan et al, 2020) and a chromatin remodeling procedure during senescence in nuclei involves the formation of senescence‐associated heterochromatin foci, where specific proliferation‐associated genes are repressed (Zhang et al, 2005). While local facultative heterochromatin is being constructed, there is a global decrease in constitutive heterochromatin in senescence—the hypothesized “heterochromatin loss model of aging” (Villeponteau, 1997).…”

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway

“…The increased SASP could cause chronic low-grade inflammation and accelerate the aging progresses in both cells and organs. 31 , 32 More and more evidence demonstrated that the chronic low-grade inflammation was one of the most important manifestations of AMD. 33 Although the precise mechanism had not been fully determined so far, we speculated that SASP was a link between aging and AMD.…”