Opposing functions of AEBP2 isoforms fine-tune PRC2 catalytic activity

Polycomb Repressive Complex 2 (PRC2) represses genes through catalyzing H3K27me3, a histone modification essential for maintenance of cellular identity. The complex’s catalytic activity, chromatin localization, and propagation along chromatin are modulated by accessory proteins such as AEBP2, MTF2, JARID2 and PALI, which is specifically required for mouse embryogenesis. AEBP2 exists in distinct isoforms: a short isoform that enhances PRC2 catalytic activity and promotes H3K27me3 spreading, facilitating robust gene repression, and a long isoform whose function has remained unclear. Here, we report that the N-terminal region of the long isoform contains a conserved DE-motif that inhibits PRC2 activity, both EZH2 automethylation and H3K27 methylation. Notably, re-expression of the long isoform in Mtf2/Jarid2/Aebp2 triple-knockout mouse embryonic stem cells failed to restore H3K27me3 and caused defective differentiation, unlike the short isoform. These findings uncover an isoform-specific regulatory mechanism by which AEBP2 controls PRC2 activity and contribute to a broader understanding of PRC2’s dynamic regulation during development