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http://dx.doi.org/10.14348/molcells.2021.0224

CHD4 Conceals Aberrant CTCF-Binding Sites at TAD Interiors by Regulating Chromatin Accessibility in Mouse Embryonic Stem Cells  

Han, Sungwook (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
Lee, Hosuk (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
Lee, Andrew J. (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
Kim, Seung-Kyoon (Department of Life Sciences, Pohang University of Science and Technology)
Jung, Inkyung (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
Koh, Gou Young (Center for Vascular Research, Institute for Basic Sciences)
Kim, Tae-Kyung (Department of Life Sciences, Pohang University of Science and Technology)
Lee, Daeyoup (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
Publication Information
Molecules and Cells / v.44, no.11, 2021 , pp. 805-829 More about this Journal
Abstract
CCCTC-binding factor (CTCF) critically contributes to 3D chromatin organization by determining topologically associated domain (TAD) borders. Although CTCF primarily binds at TAD borders, there also exist putative CTCF-binding sites within TADs, which are spread throughout the genome by retrotransposition. However, the detailed mechanism responsible for masking the putative CTCF-binding sites remains largely elusive. Here, we show that the ATP-dependent chromatin remodeler, chromodomain helicase DNA-binding 4 (CHD4), regulates chromatin accessibility to conceal aberrant CTCF-binding sites embedded in H3K9me3-enriched heterochromatic B2 short interspersed nuclear elements (SINEs) in mouse embryonic stem cells (mESCs). Upon CHD4 depletion, these aberrant CTCF-binding sites become accessible and aberrant CTCF recruitment occurs within TADs, resulting in disorganization of local TADs. RNA-binding intrinsically disordered domains (IDRs) of CHD4 are required to prevent this aberrant CTCF binding, and CHD4 is critical for the repression of B2 SINE transcripts. These results collectively reveal that a CHD4-mediated mechanism ensures appropriate CTCF binding and associated TAD organization in mESCs.
Keywords
3D chromatin organization; ATP-dependent chromatin remodeler; B2 short interspersed nuclear elements; chromodomain-helicase-DNA binding protein 4; intrinsically disordered domains; topologically associated domains;
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