Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence

• Published in: Nature communications 2020-11, Vol.11 (1), p.6049-14, Article 6049
• Main Authors: Olan, Ioana, Parry, Aled J., Schoenfelder, Stefan, Narita, Masako, Ito, Yoko, Chan, Adelyne S. L., Slater, Guy St.C., Bihary, Dóra, Bando, Masashige, Shirahige, Katsuhiko, Kimura, Hiroshi, Samarajiwa, Shamith A., Fraser, Peter, Narita, Masashi
• Format: Article
• Language: English
• Subjects: 38; 38/32; 45/15; 45/23; 45/77; 45/88; 45/91; 631/114/2114; 631/1647/2210/2211; 631/208/200; 631/337/100/101; 631/80/509; Binding; CCCTC-Binding Factor - metabolism; Cell Cycle Proteins - metabolism; Cell differentiation; Cell Differentiation - genetics; Cell fate; Cell Line; Cellular Senescence - genetics; Chromatin; Chromatin - metabolism; Chromosomal Proteins, Non-Histone - metabolism; Cohesin; Cohesins; Cohesion; Diploids; Enhancer Elements, Genetic - genetics; Fibroblasts; Folding; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetic Loci; Genome; Genomes; Homeostasis; Humanities and Social Sciences; Humans; Interleukin 1; Interleukin-1 - genetics; Macrophages; Macrophages - cytology; multidisciplinary; Phenotypes; Promoter Regions, Genetic; Protein Binding - drug effects; ras Proteins - metabolism; Science; Science (multidisciplinary); Senescence; Transcription; Transcription, Genetic; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19878-4

Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3′ end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin. Senescence is a state of stable proliferative arrest. Here, the authors perform Hi-C analysis on oncogenic RAS-induced senescence in human fibroblasts and characterize the changes in the 3D genome folding associated with the senescence-specific gene expression profile, which are mediated in part through cohesin redistribution on chromatin.