Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nat Struct Mol Biol. 2019 Mar;26(3):237-247. doi: 10.1038/s41594-019-0197-y. Epub 2019 Mar 4.
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.
多梳抑制复合物 2（PRC2）是一种组蛋白甲基转移酶，通过标记被抑制的基因和染色质区域，在多细胞生物的发育过程中维持细胞的身份。除了四个核心亚基外，PRC2 还包含多个辅助亚基，这些亚基在细胞分化过程中的组成不同，定义了两种主要的全 PRC2 复合物：PRC2.1 和 PRC2.2。PRC2 与 RNA 结合，抑制其酶活性，但 RNA 介导的全 PRC2 抑制的机制还不太清楚。在这里，我们呈现了体内和体外的蛋白质-RNA 相互作用图谱，并在人类和小鼠 PRC2 的变构调节位点内鉴定出一个 RNA 结合斑，该位点紧邻甲基转移酶中心。H3K27me3 和 JARID2-K116me3 肽的变构激活可解除全 PRC2 对 RNA 的抑制。全 PRC2.1 和全 PRC2.2 都与 RNA 结合，为解释 RNA 和变构刺激如何拮抗调节 PRC2 的酶活性提供了一个统一的模型。
