Title: The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.
Authors: Weinberg, Daniel N; Papillon-Cavanagh, Simon; Chen, Haifen; Yue, Yuan; Chen, Xiao; Rajagopalan, Kartik N; Horth, Cynthia; McGuire, John T; Xu, Xinjing; Nikbakht, Hamid; Lemiesz, Agata E; Marchione, Dylan M; Marunde, Matthew R; Meiners, Matthew J; Cheek, Marcus A; Keogh, Michael-Christopher; Bareke, Eric; Djedid, Anissa; Harutyunyan, Ashot S; Jabado, Nada; Garcia, Benjamin A; Li, Haitao; Allis, C David; Majewski, Jacek; Lu, Chao
Published In Nature, (2019 09)
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.
PubMed ID: 31485078
MeSH Terms: Animals; Cell Line; DNA (Cytosine-5-)-Methyltransferases/metabolism*; DNA Methylation*; DNA, Intergenic/metabolism*; Genome-Wide Association Study; Growth Disorders/genetics; Growth Disorders/physiopathology; Histones/metabolism*; Humans; Mice; Protein Binding; Protein Domains; Protein Transport; Sotos Syndrome/genetics; Sotos Syndrome/physiopathology