Inseparable RNA binding and chromatin modification activities of a nucleosome-interacting surface in EZH2

Polycomb repressive complex 2 (PRC2) interacts with RNAs 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.