Chd4 conceals aberrant ctcf-binding sites at tad interiors by regulating chromatin accessibility in mouse embryonic stem cells

Sungwook Han, Hosuk Lee, Andrew J. Lee, Seung Kyoon Kim, Inkyung Jung, Gou Young Koh, Tae Kyung Kim, Daeyoup Lee

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)805-829
Number of pages25
JournalMolecules and Cells
Volume44
Issue number11
DOIs
StatePublished - Nov 30 2021
Externally publishedYes

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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