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DNMT1 drives 4D genome rewiring during oncogene induced senescence

ABSTRACT: While, transcriptional and epigenetic changes associated senescence processes are well studied, the 3D chromatin changes associated with it remains elusive. In this study, we have generated genome wide chromatin interaction maps (Hi-C), epigenetic (ChIP-Seq), replication-timing and gene expression (RNA-Seq) profiles from replication induced (RS) and oncogene induced (OIS) senescent cells. As senescence associated heterochromatin foci (SAHFs) differentiates both RS and OIS nuclei, we identified the regions that constitute SAHFs and called them Senescence Associated Heterochromatin Domains (SAHDs). Further, screening of candidate factors for SAHF induction allowed us to identify DNMT1 as a novel component that induces SAHFs by stimulation of HMGA2 expression. DNMT1 depletion does not reverse the senescence process, however, instead, depleted cells transition to a 3D genome conformation akin to that of cells in replicative senescence, suggesting that acute senescence induction (OIS) involves SAHF formation in addition to the RS-dependent 3D genome rewiring.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130306 | GEO | 2020/03/27

REPOSITORIES: GEO

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Project description:Hypoxia in stem cell niches and inner core of solid tumors contributes to cellular senescence and differentiation inhibition. It directly increases histone methylationby inhibiting the activities of O2-and α-ketoglutarate (α-KG)-dependent histone lysine demethylases. This study is the first to demonstrate how the hypoxic increment of methylated histones cross-talks with other epigenetic changes, such as histone clipping and heterochromatin redistribution, named senescence-associated heterochromatin foci (SAHF), which are found during oncogene-induced senescence (OIS). This study showed that Raf activation in primary human fibroblasts IMR90 increases mature cathepsin L (CTSL)-mediated cleavage of H3, H2B, and H4. Hypoxia prevented H3 cleavage not by inhibiting CTSL but by increasing H3K18me3 and H3K23me3 nearby cleaved site of H3. Forced expression of cleaved H3 in IMR90 cells induced senescence even under hypoxia, suggesting that hypoxia breaks this positive feedback senescence driving circle by increasing methylated histones. The decrease in methylated histones is necessary for OIS to trigger histone clipping and SAHFs, but hypoxia maintains methylated histones to prevent both. Forced reduction of methylated histones in hypoxic cells using inhibitors of methyl-transferases makes hypoxic conditions unable to prevent OIS from inducing both histone clipping and SAHFs. Reversely forced enhancement of methylated histones in normoxic cells using inhibitors of histone demethylases protected histones from clipping during OIS but failed to block SAHFs. Altogether, the maintenance of methylated histones, especially H3K23me3 and H3K18me3, is sufficient to protect histones from clipping during OIS, but not for inhibiting SAHFs, suggesting that besides inhibiting KDMs, hypoxia adopts other methods to inhibit SAHFs. These findings provide a novel mechanism by which hypoxia affects cell fate by increasing methylated histones that protect histones and chromatin from dramatic epigenetic changes.

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DNMT1 drives 4D genome rewiring during oncogene induced senescence

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