Cookis Trinity, Lydecker Alexandria, Sauer Paul, Kasinath Vignesh, Nogales Eva
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA.
Nat Struct Mol Biol. 2025 Feb;32(2):393-404. doi: 10.1038/s41594-024-01452-x. Epub 2025 Jan 7.
Polycomb repressive complex 2 (PRC2) trimethylates histone H3 on K27 (H3K27me3) leading to gene silencing that is essential for embryonic development and maintenance of cell identity. PRC2 is regulated by protein cofactors and their crosstalk with histone modifications. Trimethylated histone H3 on K4 (H3K4me3) and K36 (H3K36me3) localize to sites of active transcription and inhibit PRC2 activity through unknown mechanisms. Using cryo-electron microscopy, we reveal that histone H3 tails containing H3K36me3 engage poorly with PRC2 and preclude its effective interaction with chromatin, while H3K4me3 binds to the allosteric site in the EED subunit, acting as an antagonist that competes with activators required for spreading of the H3K27me3 repressive mark. Thus, the location of the H3K4me3 and H3K36me3 modifications along the H3 tail allows them to target two requirements for efficient trimethylation of H3K27 by PRC2. We further show that the JARID2 cofactor modulates PRC2 activity in the presence of these histone modifications.
多梳抑制复合物2（PRC2）使组蛋白H3的第27位赖氨酸（H3K27）发生三甲基化，导致基因沉默，这对于胚胎发育和细胞身份维持至关重要。PRC2受蛋白质辅因子及其与组蛋白修饰的相互作用调控。第4位赖氨酸（H3K4me3）和第36位赖氨酸（H3K36me3）三甲基化的组蛋白H3定位于活跃转录位点，并通过未知机制抑制PRC2活性。利用冷冻电子显微镜，我们发现含有H3K36me3的组蛋白H3尾巴与PRC2结合不佳，阻碍其与染色质的有效相互作用，而H3K4me3结合到EED亚基的变构位点，作为拮抗剂与H3K27me3抑制标记扩散所需的激活剂竞争。因此，H3K4me3和H3K36me3修饰沿H3尾巴的位置使它们能够针对PRC2有效三甲基化H3K27的两个要求。我们进一步表明，在这些组蛋白修饰存在的情况下，JARID2辅因子调节PRC2活性。
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