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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.
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