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

Marlena Mucha1, Zhihao Lai2, Nicholas J McKenzie2

  • 1Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

The EMBO Journal
|October 31, 2025
PubMed

Insights

The accessory subunit AEBP2 has two isoforms, AEBP2L and AEBP2S, which oppositely regulate Polycomb Repressive Complex 2 (PRC2) activity. AEBP2L inhibits PRC2 in somatic cells, while AEBP2S promotes it during early development.

Area of Science:

  • Epigenetics
  • Chromatin Biology
  • Molecular Biology

Background:

  • Polycomb Repressive Complex 2 (PRC2) is crucial for H3K27 methylation, a key epigenetic mark.
  • PRC2 activity regulation is vital in development and disease, but inhibitory cofactors in somatic cells remain elusive.
  • AEBP2 was previously assumed to enhance PRC2 function.

Purpose of the Study:

  • To investigate the functional roles of alternative AEBP2 isoforms in modulating PRC2 activity.
  • To identify the mechanism by which AEBP2 isoforms regulate PRC2.
  • To understand the evolutionary significance of AEBP2 isoforms in vertebrate development.

Main Methods:

  • High-resolution cryo-electron microscopy (cryo-EM)
  • Site-directed mutagenesis
  • Analysis of AEBP2 isoform expression patterns during development

Main Results:

  • AEBP2 has two isoforms, AEBP2L (long) and AEBP2S (short), with opposing effects on PRC2.
  • AEBP2L, widely expressed, inhibits PRC2 DNA binding and methyltransferase activity.
  • AEBP2S, expressed in early embryogenesis, enhances PRC2 DNA binding for de novo gene repression.

Conclusions:

  • AEBP2L acts as an inhibitory cofactor for PRC2 in somatic cells, a function potentially evolved in vertebrates.
  • AEBP2S is essential for regulating pluripotency transitions during early embryonic development.
  • The N-terminal region of AEBP2L is identified as the inhibitory domain of PRC2.
Keywords:
AEBP2Cryo-EMPRC2PolycombTrithorax

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