The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.

中文翻译：

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PRC2的自甲基化可促进H3K27甲基化，并在H3K27M儿科神经胶质瘤中受损。

PRC2的组蛋白甲基转移酶活性对于H3K27me3修饰的兼性异染色质和基因沉默的形成至关重要。此外，PRC2已显示可对其核心亚基EZH1 / EZH2和SUZ12自甲基化。在这里，我们确定了EZH1 / EZH2被甲基化的赖氨酸残基，其中EZH2-K510和EZH2-K514是体内主要的此类位点。自甲基化的EZH2 / PRC2表现出更高水平的组蛋白甲基转移酶活性，并且是获得适当的H3K27me3细胞水平所必需的。虽然独立发生于PRC2募集到染色质上，但是自甲基化促进PRC2接近组蛋白H3尾巴。有趣的是，在组蛋白H3（H3K27M）中进行赖氨酸至蛋氨酸取代的弥漫性桥脑神经胶质瘤（DIPG）细胞中，EZH2自甲基化作用显着降低，但在携带EZH2或EED突变体的细胞中却没有，这些突变体可消除PRC2的变构激活，表明H3K27M损害了PRC2的固有活性。我们的研究通过其EZH1 / 2介导的自甲基化活性证明了PRC2的自我调节机制。