DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

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 Cai; Nelli Khudaverdyan; Burak Çetin; Dinshaw J Patel; Yinsheng Wang; Qiang Cui; Brian D Strahl; Or Gozani; Kyle M Miller; Seán E O'Leary; Paul A Wade; Gang Greg Wang; Jikui Song

doi:10.1038/s41467-021-22665-4

DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Nat Commun. 2021 May 3;12(1):2490. doi: 10.1038/s41467-021-22665-4.

Authors

Wendan Ren^#¹, Huitao Fan^#^{2

3}, Sara A Grimm⁴, Jae Jin Kim⁵, Linhui Li¹, Yiran Guo^{2

3}, Christopher James Petell^{2

3}, Xiao-Feng Tan¹, Zhi-Min Zhang¹, John P Coan⁶, Jiekai Yin⁷, Dae In Kim⁵, Linfeng Gao⁷, Ling Cai^{2

3}, Nelli Khudaverdyan¹, Burak Çetin⁸, Dinshaw J Patel⁹, Yinsheng Wang^{7

10}, Qiang Cui¹¹, Brian D Strahl^{2

3}, Or Gozani⁶, Kyle M Miller⁵, Seán E O'Leary^{1

8}, Paul A Wade⁴, Gang Greg Wang^{12

13}, Jikui Song^{14

15}

Affiliations

¹ Department of Biochemistry, University of California, Riverside, CA, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
³ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁴ Division of Intramural Research, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA.
⁵ Department of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
⁶ Department of Biology, Stanford University, Stanford, CA, USA.
⁷ Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA.
⁸ Cell, Molecular, and Developmental Biology Graduate Program, University of California, Riverside, Riverside, CA, USA.
⁹ Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Department of Chemistry, University of California, Riverside, CA, USA.
¹¹ Departments of Chemistry, Physics and Biomedical Engineering, Boston University, Boston, MA, USA.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. greg_wang@med.unc.edu.
¹³ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. greg_wang@med.unc.edu.
¹⁴ Department of Biochemistry, University of California, Riverside, CA, USA. jikui.song@ucr.edu.
¹⁵ Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA. jikui.song@ucr.edu.

^# Contributed equally.

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 (DNMT1_BAH1). Engagement of DNMT1_BAH1-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Crystallography, X-Ray
DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
DNA Methylation / genetics*
Genome / genetics
Genomic Instability / genetics
Heterochromatin / genetics
Heterochromatin / metabolism*
Histones / metabolism*
Long Interspersed Nucleotide Elements / genetics*
Mice

Substances

Heterochromatin
Histones
DNA (Cytosine-5-)-Methyltransferase 1
Dnmt1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding