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Pharmacological inhibition of EZH2 disrupts the female germline epigenome

Lexie Prokopuk1,2, Kirsten Hogg1,2, Patrick S Western1,2

  • 11Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria 3168 Australia.

Clinical Epigenetics
|March 9, 2018
PubMed
Abstract

Insights

Cancer drugs targeting EZH2 (Enhancer of Zeste 2) significantly deplete a key epigenetic mark, H3K27me3, in mouse oocytes. This depletion is long-lasting and may impact offspring development.

Area of Science:

  • Reproductive biology
  • Epigenetics
  • Developmental biology

Background:

  • Epigenetic modifying complexes are targets for novel cancer therapies.
  • Drugs targeting these complexes may impact germline epigenetic programming.
  • Enhancer of Zeste 2 (EZH2) is crucial for establishing H3K27me3 during development.

Purpose of the Study:

  • To investigate the effects of EZH1/2 inhibition on H3K27me3 in mouse oocytes.
  • To determine if H3K27me3 levels recover after drug treatment.

Main Methods:

  • Treatment of adult female mice with tazemetostat, a clinically relevant EZH1/2 inhibitor.
  • Analysis of H3K27me3 levels in growing, primary, and fetal oocytes.
  • Assessment of H3K27me3 recovery post-inhibition.

Main Results:

  • Tazemetostat severely depleted H3K27me3 in growing oocytes.
  • H3K27me3 was also depleted in primary and fetal oocytes.
  • H3K27me3 failed to recover in oocytes after EZH1/2 inhibition.

Conclusions:

  • Drugs targeting EZH2 significantly impact the germline epigenome.
  • Oocyte-specific loss of EZH2 function suggests potential effects on offspring outcomes.
  • Further research is needed to understand the long-term consequences for reproductive health.
Keywords:
EpigeneticGermlineH3K27me3InheritanceOocytePRC2Pharmacology

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