Cancer-Associated DNMT3A Is Recruited by H3K36me2 to Methylate DNA

The DNA methyltransferase DNMT3A, which methylates CpG dinucleotides, has been implicated in a variety of cancers. Weinberg, Papillon-Cavanagh, and colleagues report that DNMT3A colocalized with regions bearing high levels of CpG methylation and histone H3 dimethylated at lysine residue 36 (H3K36me2), an epigenetic mark associated with active transcription and neighboring intergenic regions, in mouse mesenchymal stem cells (MSC). Experiments in mouse embryonic stem cells lacking DNA methylation in which reexpression of the predominant DNMT3A isoform (DNMT3A2) had been established revealed that de novo methylation activity of DNMT3A correlated with the level of H3K36me2. Additionally, maintenance of CpG methylation and the intergenic localization of DNMT3A required H3K36me2 deposited by the histone methyltransferase NSD1. Biochemical experiments showed that the PWWP “reader” domain of DNMT3A (DNMT3A_PWWP) exhibited preferential binding of H3K36me2 compared with other modified histones; this binding occurred with high affinity, and DNMT3A_PWWP also exhibited weaker affinity for trimethylated H3K36 (H3K36me3). In mouse MSCs in which Nsd1 and the related histone methyltransferase–encoding gene Nsd2 had been genetically ablated, DNMT3A was redistributed from intergenic regions to gene bodies containing high levels of H3K36me3, suggesting that the localization of DNMT3A is guided by its PWWP domain's affinity for H3K36me2 (and, to a smaller degree, H3K36me3). Illustrating the relevance of these findings in human cancer, profiling of H3K36me2 and CpG methylation in patient-derived head and neck squamous cell carcinoma cell lines indicated that low CpG methylation levels correlated with genome-wide reductions (primarily at intergenic regions) in NSD1-mutant lines compared with an NSD1–wild-type line. Together, these results provide a basis for understanding the role of DNMT3A in disease and, more broadly, for learning how the DNA-methylation landscape is established and maintained.

Weinberg DN, Papillon-Cavanagh S, Chen H, Yue Y, Chen X, Rajagopalan KN, et al. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature 2019;573:281–6.

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