期刊
NATURE
卷 573, 期 7773, 页码 281-+出版社
NATURE RESEARCH
DOI: 10.1038/s41586-019-1534-3
关键词
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资金
- US National Institutes of Health (NIH) [P01CA196539, R00CA212257, T32GM007739, F30CA224971, T32GM008275, R44GM116584, R44GM117683]
- Rockefeller University
- Cedars Cancer Foundation
- NIH/NCI Cancer Center Support Grant [P30CA013696]
- Genome Canada
- Genome Quebec
- Institute for Cancer Research of the CIHR, McGill University
- Montreal Children's Hospital Foundation
- National Natural Science Foundation of China [31725014, 91753203]
- Damon Runyon Foundation [DFS-28-18]
- AACR Gertrude B. Elion Cancer Research Grant
- Fond de la Recherche du Quebec en Sante
- Leukemia and Lymphoma Society Dr. Robert Arceci Scholar Award
- NATIONAL CANCER INSTITUTE [P01CA196539] Funding Source: NIH RePORTER
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 homeostasis(1-4). They are also implicated in human developmental disorders and cancers(5-8), 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 bodies(9-11). 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.
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