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EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity.

Jeffrey Granat1,2, Sanxiong Liu1,2,3,4,5, Luis Popoca1,2

  • 1HHMI, New York University Langone Health, New York, NY 10016.

Proceedings of the National Academy of Sciences of the United States of America
|February 6, 2026
PubMed
Summary
This summary is machine-generated.

The study reveals that EPOP protein enhances Polycomb Repressive Complex 2 (PRC2) histone methyltransferase activity, crucial for gene regulation. EPOP, along with MTF2 and JARID2, promotes H3K27me3 deposition at specific DNA sequences.

Keywords:
PRC2epigeneticsrepressive chromatintranscription

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Area of Science:

  • Epigenetics
  • Molecular Biology
  • Chromatin Biology

Background:

  • Polycomb Repressive Complex 2 (PRC2) is essential for facultative heterochromatin formation and tissue-specific gene expression.
  • PRC2 catalyzes histone H3 lysine 27 trimethylation (H3K27me3), a mark targeted by PRC1 for chromatin compaction.
  • Cofactors like MTF2 and JARID2 guide PRC2 to specific DNA motifs, regulating its activity.

Purpose of the Study:

  • To investigate the role of EPOP in regulating PRC2 activity and H3K27me3 deposition.
  • To determine if EPOP influences PRC2 chromatin recruitment or catalytic activity.
  • To elucidate the cooperative mechanisms of EPOP, MTF2, and JARID2 in PRC2 function.

Main Methods:

  • In vitro histone methyltransferase (HMT) assays to measure PRC2 activity.
  • In vivo EED-rescue system to assess PRC2 chromatin recruitment.
  • Dinucleosome binding assays to evaluate PRC2-DNA sequence preference.

Main Results:

  • EPOP and MTF2 both stimulate PRC2 HMT activity in vitro.
  • EPOP does not mediate PRC2 chromatin recruitment in vivo but cooperates with MTF2 and JARID2 for de novo H3K27me3 deposition.
  • EPOP enhances PRC2 chromatin binding in a DNA-sequence-dependent manner (GCN-rich sequences).

Conclusions:

  • EPOP acts as a positive regulator of PRC2 catalytic activity, distinct from its role in chromatin recruitment.
  • EPOP, MTF2, and JARID2 collaborate to promote H3K27me3 deposition at specific DNA sequences, contributing to H3K27me3-chromatin domain formation.