Distinct regulation of AEBP2 isoforms on PRC2 activity

Polycomb Repressive Complex 2 (PRC2) represses gene expression through catalyzing H3K27me3, a histone modification essential for gene repression and maintenance of cellular identity. PRC2 accessory proteins modulate its catalytic activity, chromatin localization, and propagation along the chromatin. AEBP2, one of the PRC2 accessory proteins required for mouse embryogenesis, exists in distinct isoforms. The short isoform enhances PRC2 catalytic activity and promotes H3K27me3 spreading, facilitating robust gene repression while the function of the long isoform has remained unclear. Here, we found that the N-terminal region of AEBP2 long isoform contains a conserved DE-rich motif that inhibits PRC2 activity, both EZH2 automethylation and H3K27 methylation. In addition, re-expression of the AEBP2 long isoform in Mtf2 / Jarid2 / Aebp2 triple-knockout mESCs failed to restore H3K27me3 and caused defective differentiation, unlike the short isoform. Together, our findings uncover an isoform-specific regulatory mechanism by which AEBP2 controls PRC2 activity and contribute to a broader understanding of how PRC2 is dynamically regulated during development.