SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates

Tushar Warrier, Chadi El Farran, Yingying Zeng, Benedict Shao Quan Ho, Qiuye Bao, Zi Hao Zheng, Xuezhi Bi, Huck Hui Ng, Derrick Sek Tong Ong, Justin Jang Hann Chu, Amartya Sanyal, Melissa Jane Fullwood, James J. Collins, Hu Li, Jian Xu, Yuin Han Loh

Research output: Contribution to journalArticlepeer-review


SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these nonH3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene 'islands' that drive differentiation to other lineages. The 'unearthing' of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.

Original languageEnglish (US)
Pages (from-to)7326-7349
Number of pages24
JournalNucleic acids research
Issue number13
StatePublished - Jul 22 2022

ASJC Scopus subject areas

  • Genetics


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