Cryo-EM structures of Arabidopsis PRC2 histone methyltransferase isoforms reveal a differential regulatory mechanism

Polycomb Repressive Complex 2 (PRC2) is a histone H3K27 methyltransferase that represses gene expression. Arabidopsis thaliana (A. thaliana) has several different PRC2 isoforms that are functionally distinct during the life cycle of the plants. However, their biochemical and structural characteristics have not been investigated. Here, we biochemically characterized PRC2 isoforms having different catalytic subunits: SWNINGER (SWN; PRC2 SWN ) and CURLY LEAF (CLF; PRC2 CLF ). Interestingly, PRC2 SWN showed much lower activity than PRC2 CLF . In addition, PRC2 SWN methylates histone H3K27 in mono and di-methylation, while PRC2 CLF shows robust tri-methylase activity. We also determined the cryo-electron microscopy (cryo-EM) structures of PRC2 SWN and PRC2 CLF , revealing that the substrate binding pocket of the SWN SET domain is blocked by a loop in the pre-SET domain, functioning as an auto-inhibitory loop, while that of the CLF SET domain is freely accessible. Introduction of CLF-like mutations in the auto-inhibitory loop in SWN enhances PRC2 SWN activity. Furthermore, structure-guided in planta analysis shows that a CLF-mimetic SWN mutant rescues the CLF knockout phenotype. Our work provides structural and molecular insights into the isoform-specific regulatory mechanism of plant PRC2.