Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

Wendan Ren; Huitao Fan; Sara A Grimm; Yiran Guo; Jae Jin Kim; Jiekai Yin; Linhui Li; Christopher J Petell; Xiao-Feng Tan; Zhi-Min Zhang; John P Coan; Linfeng Gao; Ling Cai; Brittany Detrick; Burak Çetin; Qiang Cui; Brian D Strahl; Or Gozani; Yinsheng Wang; Kyle M Miller; Seán E O'Leary; Paul A Wade; Dinshaw J Patel; Gang Greg Wang; Jikui Song

doi:10.1073/pnas.2009316117

Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18439-18447. doi: 10.1073/pnas.2009316117. Epub 2020 Jul 16.

Authors

Wendan Ren¹, Huitao Fan^{2

3}, Sara A Grimm⁴, Yiran Guo^{2

3}, Jae Jin Kim⁵, Jiekai Yin⁶, Linhui Li¹, Christopher J Petell^{2

3}, Xiao-Feng Tan¹, Zhi-Min Zhang¹, John P Coan⁷, Linfeng Gao⁶, Ling Cai^{2

3}, Brittany Detrick¹, Burak Çetin⁸, Qiang Cui^{9

10

11}, Brian D Strahl^{2

3}, Or Gozani⁷, Yinsheng Wang^{6

12}, Kyle M Miller⁵, Seán E O'Leary^{1

8}, Paul A Wade⁴, Dinshaw J Patel¹³, Gang Greg Wang^{14

3}, Jikui Song^{15

6}

Affiliations

¹ Department of Biochemistry, University of California, Riverside, CA 92521.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.
³ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.
⁴ Division of Intramural Research, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC 27709.
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 78712.
⁶ Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521.
⁷ Department of Biology, Stanford University, Stanford, CA 94305.
⁸ Cell, Molecular, and Developmental Biology Graduate Program, University of California, Riverside, CA 92521.
⁹ Department of Chemistry, Boston University, Boston, MA 02215.
¹⁰ Department of Physics, Boston University, Boston, MA 02215.
¹¹ Department of Biomedical Engineering, Boston University, Boston, MA 02215.
¹² Department of Chemistry, University of California, Riverside, CA 92521.
¹³ Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065 pateld@mskcc.org greg_wang@med.unc.edu jikui.song@ucr.edu.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599; pateld@mskcc.org greg_wang@med.unc.edu jikui.song@ucr.edu.
¹⁵ Department of Biochemistry, University of California, Riverside, CA 92521; pateld@mskcc.org greg_wang@med.unc.edu jikui.song@ucr.edu.

Abstract

In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

Keywords: DNA methylation; DNMT1; H3K9me3; allosteric regulation.

Publication types

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

MeSH terms

DNA (Cytosine-5-)-Methyltransferase 1 / genetics
DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
DNA Methylation*
Heterochromatin / genetics
Heterochromatin / metabolism*
Histones / chemistry
Histones / genetics
Histones / metabolism*
Humans
Lysine / genetics
Lysine / metabolism
Methylation
Protein Processing, Post-Translational

Substances

Heterochromatin
Histones
DNA (Cytosine-5-)-Methyltransferase 1
DNMT1 protein, human
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding