Emerging structural insights into PRC2 function in development and disease

Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.