SETDB1 Acts as a Topological Accessory to Cohesin via an H3K9me3-independent, Genomic Shunt for Regulating Cell Fates (Nucleic Acids Res, Jul 2022)

Tushar Warrier 1 2Chadi El Farran 1 2Yingying Zeng 1 3Benedict Shao Quan Ho 1Qiuye Bao 1Zi Hao Zheng 1 4Xuezhi Bi 5Huck Hui Ng 6Derrick Sek Tong Ong 4Justin Jang Hann Chu 7 8Amartya Sanyal 3Melissa Jane Fullwood 3 9James J Collins 10 11 12 13Hu Li 14Jian Xu 2 15Yuin-Han Loh 1 2 4 16


  • 1Cell Fate Engineering and Therapeutics Lab, Cell Biology and Therapies Division, A*STAR Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
  • 2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
  • 3School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive 637551, Singapore.
  • 4Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
  • 5Proteomics Group, Bioprocessing Technology Institute, A*STAR, Singapore 138668, Singapore.
  • 6Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672, Singapore.
  • 7Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
  • 8Infectious Disease Translational Research Programme, National University of Singapore, Singapore 117597, Singapore.
  • 9Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
  • 10Howard Hughes Medical Institute, Boston, MA 02114, USA.
  • 11Institute for Medical Engineering and Science Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02114, USA.
  • 12Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
  • 13Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
  • 14Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 15Department of Plant Systems Physiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
  • 16NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 MedicalDrive, Singapore 117456, Singapore.


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 non-H3K9me3 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.

PMID: 35776115  DOI: 10.1093/nar/gkac531