8EQV

Cryo-EM structure of PRC2 in complex with the long isoform of AEBP2

Summary for 8EQV

• Entry DOI: 10.2210/pdb8eqv/pdb
• EMDB information: 28547
• Descriptor: Histone-binding protein RBBP4, Zinc finger protein AEBP2, Polycomb protein EED, ... (5 entities in total)
• Functional Keywords: polycomb repressive complex 2 histone methyltransferase, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 321186.93

Authors

Boudes, M.,Zhang, Q.,Flanigan, S.F.,Davidovich, C. (deposition date: 2022-10-09, release date: 2024-07-31, Last modification date: 2025-12-03)

Primary citation

Mucha, M.,Lai, Z.,McKenzie, N.J.,Matra, F.,Boudes, M.,Flanigan, S.F.,Alejo-Vinogradova, M.T.,Monger, C.,Zhang, Q.,Nimmo, D.,Healy, E.,Silva, A.J.,Angelov, D.,Reck, D.M.,Holland, G.,Atmaca, Z.E.,King, H.E.,Hamilton, M.,Glancy, E.,Nolan, J.,Weatheritt, R.J.,Bell, O.,Vermeulen, M.,Davidovich, C.,Bracken, A.P.
Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
Embo J., 2025

PubMed Abstract: 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 (short) and AEBP2 (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2 isoform inhibits it. AEBP2 is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2, 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 inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2 arose in vertebrates to restrain PRC2 activity in somatic cells.

PubMed: 41168462
DOI: 10.1038/s44318-025-00616-9

Experimental method

ELECTRON MICROSCOPY (3.64 Å)