How do cells tune PRC2 allostery? We find EZH2 Ser21-phos restrains PRC2 adoption of the compact active state. Loss of this restraint promotes H3K27me3, redistributes cPRC1, and impairs differentiation. New bioRxiv with @kasinath-lab.bsky.social & @garcialabms.bsky.social! tinyurl.com/4369kmh2