Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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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)
  • Received : 2021.08.31
  • Accepted : 2021.09.06
  • Published : 2021.11.30
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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

Acknowledgement

We thank Taemook Kim and Prof. Keunsoo Kang for assistance with analyzing the NGS data; Kwang-Beom Hyun and Prof. Jaehoon Kim for purification of CHD4 protein using the Bac-to-Bac Baculovirus expression system (Full-length cDNA of mouse Chd4 was purchased from Open Biosystems, MMM1013-202770503). This work was supported by a National Research Foundation of Korea grant funded by the Ministry of Science and ICT (MSIT) (2018R1A5A1024261, SRC), and the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the MSIT (2018M3C9A6065070).

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