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EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells.

Roberta Ragazzini1, Raquel Pérez-Palacios1, Irem H Baymaz2

  • 1Institut Curie, PSL Research University, Sorbonne University, INSERM U934/ CNRS UMR3215, 26, rue d'Ulm, 75005, Paris, France.

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|August 28, 2019
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We identified EZHIP, a new regulator of Polycomb Repressive Complex 2 (PRC2) in the gonads. Loss of EZHIP impairs fertility by altering H3K27me2/3 levels during gamete development.

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Area of Science:

  • Epigenetics
  • Molecular Biology
  • Reproductive Biology

Background:

  • Polycomb group proteins, including Polycomb Repressive Complex 2 (PRC2), are crucial for maintaining transcriptional silencing and proper gene expression.
  • PRC2 deposits the H3K27me2/3 mark, a key epigenetic modification involved in developmental processes.

Purpose of the Study:

  • To identify and characterize novel cofactors of PRC2, particularly those involved in gametogenesis.
  • To investigate the function of EZHIP (EZH1/2 Inhibitory Protein) in regulating PRC2 activity and its impact on fertility.

Main Methods:

  • Identification of EZHIP as a PRC2 cofactor.
  • Analysis of EZHIP expression patterns, predominantly in gonads.
  • Assessment of PRC2 enzymatic activity and chromatin interaction in the presence and absence of EZHIP.
  • Generation and analysis of Ezhip knockout mice to study its in vivo function during spermatogenesis and oogenesis.

Main Results:

  • EZHIP acts as a cofactor that limits PRC2 enzymatic activity and reduces core complex interactions without affecting chromatin recruitment.
  • Ezhip deletion in mice results in increased global H3K27me2/3 deposition during spermatogenesis and late oocyte maturation.
  • While initial follicle numbers are unaffected, Ezhip deficiency leads to follicle reduction in aging and impaired oocyte function, strongly reducing female fertility.

Conclusions:

  • EZHIP is a novel regulator of the chromatin landscape specifically within gametes.
  • The regulation of PRC2 activity by EZHIP is critical for maintaining fertility and proper gamete maturation.
  • Dysregulation of EZHIP can lead to epigenetic alterations and reproductive challenges.