SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates
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gkac531.pdf
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Published version
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5.75 MB
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Checksum (MD5)
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Author(s)
Warrier, Tushar
El Farran, Chadi
Zeng, Yingying
Ho, Benedict Shao Quan
Bao, Qiuye
Zheng, Zi Hao
Bi, Xuezhi
Ng, Huck Hui
Ong, Derrick Sek Tong
Chu, Justin Jang Hann
Date Issued
July 22, 2022
Journal
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Citation
Warrier, Tushar, El Farran, Chadi, Zeng, Yingying, Ho, Benedict Shao Quan, Bao, Qiuye et al. 2022. "SETDB1 acts as a topological accessory to Cohesin via an H3K9me3-independent, genomic shunt for regulating cell fates." Nucleic Acids Research, 50 (13).
Version
Final published version
Abstract
Abstract
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.
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
https://doi.org/10.1093/nar/gkac531
