The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/ EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.

The catalytic activity of PRC2 is central to maintain transcriptional repression by H3K27me3-decorated facultative heterochromatin in mammalian cells. To date, multiple factors have been reported to regulate PRC2 activity. Here, we demonstrate that PRC2 methylates itself on EZH1/2 and SUZ12 subunits, with EZH1/2-K514 being the major automethylation site in cells. The functional studies of automethylation on EZH2 indicate automethylation as a self-activating mechanism for PRC2 in the absence of stimulatory cofactors like AEBP2. Together, our study reveals PRC2 automethylation as a novel regulatory mechanism of PRC2 activity on chromatin.