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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Author

Listed:
  • Wendan Ren

    (University of California)

  • Huitao Fan

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Sara A. Grimm

    (National Institute of Environmental Health Sciences, Research Triangle Park)

  • Jae Jin Kim

    (University of Texas at Austin)

  • Linhui Li

    (University of California)

  • Yiran Guo

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Christopher James Petell

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Xiao-Feng Tan

    (University of California)

  • Zhi-Min Zhang

    (University of California)

  • John P. Coan

    (Stanford University)

  • Jiekai Yin

    (University of California)

  • Dae In Kim

    (University of Texas at Austin)

  • Linfeng Gao

    (University of California)

  • Ling Cai

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Nelli Khudaverdyan

    (University of California)

  • Burak Çetin

    (University of California, Riverside)

  • Dinshaw J. Patel

    (Memorial Sloan Kettering Cancer Center)

  • Yinsheng Wang

    (University of California
    University of California)

  • Qiang Cui

    (Boston University)

  • Brian D. Strahl

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Or Gozani

    (Stanford University)

  • Kyle M. Miller

    (University of Texas at Austin)

  • Seán E. O’Leary

    (University of California
    University of California, Riverside)

  • Paul A. Wade

    (National Institute of Environmental Health Sciences, Research Triangle Park)

  • Gang Greg Wang

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Jikui Song

    (University of California
    University of California)

Abstract

DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

Suggested Citation

  • Wendan Ren & Huitao Fan & Sara A. Grimm & Jae Jin Kim & Linhui Li & Yiran Guo & Christopher James Petell & Xiao-Feng Tan & Zhi-Min Zhang & John P. Coan & Jiekai Yin & Dae In Kim & Linfeng Gao & Ling C, 2021. "DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22665-4
    DOI: 10.1038/s41467-021-22665-4
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    Cited by:

    1. Zhengyi Zhen & Yu Chen & Haiyan Wang & Huanyin Tang & Haiping Zhang & Haipeng Liu & Ying Jiang & Zhiyong Mao, 2023. "Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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