Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence
- Abstract:
- Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis 1,2 . Enhancer-promoter interactions play a key role in gene regulation 3–5 , facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering 6–8 . The three-dimensional chromatin structure of senescent cells has been characterised 9–11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. Here, we use Hi-C and capture Hi-C 12,13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3’ end of a subset of active genes, reminiscent of the transcription-driven ‘cohesin islands’ recently discovered in mouse embryonic fibroblasts deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl) 14 . RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancer-promoter rewiring during the terminal differentiation of monocytes to macrophages 15 , but not upon acute TNFα treatment of HDFs 16 . These results suggest that RIS represents a fate-determined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution.
- Authors:
- I Olan, A Parry, S Schoenfelder, M Narita, Y Ito, ASL Chan, GSC Slater, D Bihary, M Bando, K Shirahige, H Kimura, S Samarajiwa, P Fraser, M Narita
- Publication date:
- 1st Aug 2019
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- DOI