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

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hdl_148526.pdf (6.04 MB)
  (Published version)

Date

2025

Authors

Mucha, M.
Lai, Z.
McKenzie, N.J.
Matrà, F.
Boudes, M.
Flanigan, S.F.
Alejo-Vinogradova, M.T.
Monger, C.
Zhang, Q.
Nimmo, D.

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Journal article

Citation

EMBO Journal, 2025; 44(23):6979-7020

Statement of Responsibility

Marlena Mucha, Zhihao Lai, Nicholas J McKenzie, Francesca Matrà, Marion Boudes, Sarena F Flanigan, Maria Teresa Alejo-Vinogradova, Craig Monger, Qi Zhang, Darragh Nimmo, Evan Healy, Ademar J Silva, Daniel Angelov, David M Reck, Gráinne Holland, Zeynep Eda Atmaca, Helen E King, Maeve Hamilton, Eleanor Glancy, James Nolan, Robert J Weatheritt, Oliver Bell, Michiel Vermeulen, Chen Davidovich, Adrian P Bracken

Conference Name

DOI

10.1038/s44318-025-00616-9

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 AEBP2S (short) and AEBP2L (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2L isoform inhibits it. AEBP2L is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2S, 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 AEBP2L inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2L arose in vertebrates to restrain PRC2 activity in somatic cells.

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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.

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http://purl.org/au-research/grants/nhmrc/1162921
 http://purl.org/au-research/grants/nhmrc/1196365
 http://purl.org/au-research/grants/arc/DP190103407
 http://purl.org/au-research/grants/arc/FT240100821
 http://purl.org/au-research/grants/arc/DP250104894
 http://purl.org/au-research/grants/nhmrc/1184637
 http://purl.org/au-research/grants/nhmrc/2011767
 http://purl.org/au-research/grants/nhmrc/2020900

Published Version

https://doi.org/10.1038/s44318-025-00616-9

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Persistent link to this record

https://hdl.handle.net/2440/148526