The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.
|核心内容：
催化DNA中CpG甲基化的酶，包括DNA甲基转移酶1(DNMT1)、3A(DNMT3A)和3B(Dnmt3b)，对于哺乳动物组织发育和动态平衡是必不可少的。 它们还与人类发育障碍和癌症有关，支持DNA甲基化在指定和维持细胞命运中的关键作用。以前的研究表明，组蛋白的翻译后修饰参与了DNA甲基转移酶定位和DNA甲基化在启动子和活跃转录的基因体的模式。 然而，控制基因间DNA甲基化建立和维持的机制仍然知之甚少。Tatton-Brown-Rahman综合征(Tatton-Brown-Rahman syndrome，TBRS)是一种由DNMT3A基因种系突变定义的儿童过度生长障碍。 TBRS的临床特征与Sotos综合征相似(由NSD1单倍体不足引起，NSD1是一种组蛋白甲基转移酶，催化组蛋白H3在K36位(H3K36me2)的二甲基化)，这表明这两种疾病之间存在机制联系。 在此，我们报道了NSD1介导的H3K36me2对于DNMT3A的招募和维持基因间隔区的DNA甲基化是必需的。 全基因组分析表明，DNMT3A与H3K36me2的结合和活性共定位在常染色质的非编码区。在小鼠细胞中基因消融NSD1及其类似物Nsd2导致DNMT3A重新分布到H3K36me3修饰的基因体上，并减少基因间DNA的甲基化。 Sotos综合征和NSD1突变肿瘤患者的血液样本也显示出基因间DNA的低甲基化。 DNMT3A的PWWP结构域在体外表现出对H3K36me2和H3K36me3的双重识别，与被TBRs衍生的错义突变所破坏的H3K36me2有更高的结合亲和力。 总之，我们的研究揭示了一个跨染色质调控途径，它将基因间异常的CpG甲基化与人类肿瘤和发育过度联系起来。
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. They are also implicated in human developmental disorders and cancers, 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. 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)), 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.
参考文献：Weinberg Daniel N,Papillon-Cavanagh Simon,Chen Haifen et al. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.[J] .Nature, 2019, 573: 281-286.
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