2. Academic Validation
  3. A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association

A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association

  • Nucleic Acids Res. 2020 Dec 2;48(21):12116-12134. doi: 10.1093/nar/gkaa1003.
Mengmeng Han 1,  Jialun Li 1 2,  Yaqiang Cao 3,  Yuanyong Huang 1,  Wen Li 1,  Haijun Zhu 4,  Qian Zhao 1,  Jing-Dong Jackie Han 3,  Qihan Wu 4,  Jiwen Li 1,  Jing Feng 2 5,  Jiemin Wong 1 2
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China.
  • 3 CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Room122, 320 Yue Yang Road, Shanghai 200031, China.
  • 4 NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 200032, China.
  • 5 Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China.
PMID: 33170271 DOI: 10.1093/nar/gkaa1003
Abstract

LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.

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