DNMT1 drives 4D genome rewiring during oncogene induced senescence

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.