Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma
Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma
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DOI：
10.1101/gad.328773.119
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发表时间：
2019-10-01
影响因子：
10.5
通讯作者：
Reinberg, Danny
中科院分区：
文献类型：
--
作者：
Lee, Chul-Hwan;Yu, Jia-Ray;Reinberg, Danny
PRC 2的组蛋白甲基转移酶活性对于H3 K27 me 3修饰的兼性异染色质和基因沉默的形成至关重要。此外，PRC 2已被证明可以使其核心亚基EZH 1/EZH 2和SUZ 12自动甲基化。在此，我们鉴定了EZH 1/EZH 2自甲基化的赖氨酸残基，其中EZH 2-K510和EZH 2-K514是体内主要的此类位点。自甲基化的EZH 2/PRC 2表现出更高水平的组蛋白甲基转移酶活性，并且是获得H3 K27 me 3的适当细胞水平所需的。虽然自甲基化独立于PRC 2向染色质的募集而发生，但自甲基化促进PRC 2接近组蛋白H3尾部。有趣的是，EZH 2自甲基化在组蛋白H3（H3 K27 M）中携带赖氨酸至甲硫氨酸取代的弥漫性内在脑桥胶质瘤（DIPG）细胞中显著减少，但在携带EZH 2或EED突变体的细胞中不显著减少，所述突变体消除PRC 2变构激活，表明H3 K27 M损害PRC 2的内在活性。我们的研究证明了PRC 2通过其EZH 1/2介导的自甲基化活性的自我调节机制。
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.