Abstract
Chromatin organization and transcriptional profiles undergo tremendous reordering during senescence. However, uncovering the regulatory mechanisms between chromatin reconstruction and gene expression in senescence has been elusive. Here, we depicted the landscapes of both chromatin accessibility and gene expression to reveal gene regulatory networks in human umbilical vein endothelial cell (HUVEC) senescence and found that chromatin accessibilities are redistributed during senescence. Particularly, the intergenic chromatin was massively shifted with the increased accessibility regions (IARs) or decreased accessibility regions (DARs), which were mainly enhancer elements. We defined AP‐1 transcription factor family as being responsible for driving chromatin accessibility reconstruction in IARs, where low DNA methylation improved binding affinity of AP‐1 and further increased the chromatin accessibility. Among AP‐1 transcription factors, we confirmed ATF3 was critical to reconstruct chromatin accessibility to promote cellular senescence. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program, we identified that AP‐1 was capable of reorganizing the chromatin accessibility profile to regulate senescence.
Highlights
Cellular senescence is known as an irreversible cell-cycle arrest further bringing a series of progressive cellular states and phenotypic changes(van Deursen, 2014)
We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in increased accessible regions (IARs)
Our results revealed that the chromatin accessibility profile was rearranged during senescence, and there were some senescence specific regions with regular changes in accessibility, of which IARs are mainly distributed in heterochromatin that already defined and decreased accessible regions (DARs) are mainly distributed in known weak enhancers and promoters
Summary
Cellular senescence is known as an irreversible cell-cycle arrest further bringing a series of progressive cellular states and phenotypic changes(van Deursen, 2014). In many candidate hallmarks that may contribute to aging(Lopez-Otin, Blasco, Partridge, Serrano, & Kroemer, 2013), epigenetic alterations including spontaneous or passive changes are pretty compelling. Epigenetics has been considered an extremely important contributor to senescence and aging(Fraga et al, 2005; Payel Sen, Shah, Nativio, & Berger, 2016). Histone modifications reflect the different status of chromatin structures and we can investigate the regulatory mechanism of senescence and aging based on the varying patterns of histone modifications. 2015), decrease of H4K16ac is observed in Zmpste-24-null fibroblasts(Krishnan et al, 2011), loss of H4K20me promotes senescence and aging (Lyu et al, 2018)
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