Polycomb repressive complex 2 (PRC2) interacts with RNA in cells, but there is no consensus on how RNA regulates PRC2 canonical functions, including chromatin modification and the maintenance of transcription programs in lineage-committed cells. We assayed two separation-of-function mutants of the PRC2 catalytic subunit EZH2, defective in RNA binding but functional in methyltransferase activity. We find that part of the RNA-binding surface of EZH2 is required for chromatin modification, yet this activity is independent of RNA. Mechanistically, the RNA-binding surface within EZH2 is required for chromatin modification in vitro and in cells, through interactions with nucleosomal DNA. Contrarily, an RNA-binding-defective mutant exhibited normal chromatin modification activity in vitro and in lineage-committed cells, accompanied by normal gene repression activity. Collectively, we show that part of the RNA-binding surface of EZH2, rather than the RNA-binding activity per se, is required for the histone methylation in vitro and in cells, through interactions with the substrate nucleosome.

Polycomb 抑制复合物 2 (PRC2) 与细胞中的 RNA 相互作用，但对于 RNA 如何调节 PRC2 的典型功能（包括染色质修饰和谱系定型细胞中转录程序的维持）尚未达成共识。我们检测了 PRC2 催化亚基 EZH2 的两个功能分离突变体，它们在 RNA 结合方面存在缺陷，但在甲基转移酶活性方面具有功能。我们发现 EZH2 的部分 RNA 结合表面是染色质修饰所必需的，但这种活性与 RNA 无关。从机制上讲，EZH2 内的 RNA 结合表面是体外和细胞内染色质修饰所必需的，通过与核小体 DNA 的相互作用。相反，RNA结合缺陷突变体在体外和谱系定型细胞中表现出正常的染色质修饰活性，并伴有正常的基因抑制活性。总的来说，我们发现 EZH2 的部分 RNA 结合表面，而不是 RNA 结合活性本身，是体外和细胞内组蛋白甲基化所必需的，通过与底物核小体的相互作用。