Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence

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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>IL1B</jats:italic>, where de novo cohesin binding is involved in new loop formation. Similar <jats:italic>IL1B</jats:italic> 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.</jats:p>

Journal

  • Nature Communications

    Nature Communications 11 (1), 6049-, 2020-11-27

    Springer Science and Business Media LLC

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