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Nature. 2019 Sep;573(7773):281-286. doi: 10.1038/s41586-019-1534-3. Epub 2019 Sep 4.

The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA.
2
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
3
MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.
4
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
5
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
6
Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, New York, NY, USA.
7
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8
Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
EpiCypher Inc, Durham, NC, USA.
10
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
11
Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
12
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA. alliscd@rockefeller.edu.
13
Department of Human Genetics, McGill University, Montreal, Quebec, Canada. jacek.majewski@mcgill.ca.
14
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA. cl3684@cumc.columbia.edu.
15
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. cl3684@cumc.columbia.edu.

Abstract

Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1-4. They are also implicated in human developmental disorders and cancers5-8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9-11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

PMID:
31485078
PMCID:
PMC6742567
[Available on 2020-03-04]
DOI:
10.1038/s41586-019-1534-3

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