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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • 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

摘要

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.