Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.

Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri-methylating H3K27. Control of PRC2 activity is a critical process in development and disease, yet no inhibitory cofactor has been identified in somatic cells. Here, we show that the alternative isoforms of its accessory subunit AEBP2, namely AEBP2^S (short) and AEBP2^L (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2^L isoform inhibits it. AEBP2^L is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2^S, expressed during early embryogenesis, promotes PRC2 DNA-binding activity and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2^L inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2^L arose in vertebrates to restrain PRC2 activity in somatic cells.