通过染色质上的二聚化激活自动甲基化的 PRC2

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cell Pub Date : 2024-09-19 DOI:10.1016/j.molcel.2024.08.025
Paul V. Sauer, Egor Pavlenko, Trinity Cookis, Linda C. Zirden, Juliane Renn, Ankush Singhal, Pascal Hunold, Michaela N. Hoehne-Wiechmann, Olivia van Ray, Farnusch Kaschani, Markus Kaiser, Robert Hänsel-Hertsch, Karissa Y. Sanbonmatsu, Eva Nogales, Simon Poepsel
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引用次数: 0

摘要

多聚胞抑制复合体 2(PRC2)是一种表观遗传调控因子,可对组蛋白 3 的 27 号赖氨酸(H3K27me3)进行三甲基化,对胚胎发育和细胞分化至关重要。H3K27me3 与转录抑制染色质有关,当 PRC2 被调节亚基 EED 结合甲基赖氨酸后异源激活时,H3K27me3 就会形成。催化亚基泽斯特同源增强子 2(EZH2)的自甲基化通过一种未知的机制刺激其活性。在这里,我们展示了人类 PRC2 在染色质上形成的二聚体,其中一个非活性、自甲基化的 PRC2 原体是第二个 PRC2 的异位激活剂,后者准备甲基化底物核小体的 H3。功能测试支持了我们通过 EED 进行异生反式自激活的模型,这表明了一种以前未知的介导 PRC2 上下文依赖性激活的机制。我们的工作展示了自动修饰耦合二聚化在调控染色质修饰复合物中的分子机制。
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Activation of automethylated PRC2 by dimerization on chromatin

Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes.

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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
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