Oral Presentation ESA-SRB-APEG-NZSE 2022

PRC2 subunits, EZH2 and EED, have differential contributions to epigenetic programming in oocytes (#116)

Ellen Jarred 1 2 , Tesha Tsai 1 2 3 , Zhipeng Qu 4 , Ruby Oberin 1 2 , Sigrid Petautschnig 1 2 , Heidi Bildsoe 1 2 , Stephen Pederson 4 , David Adelson 4 , Qinghua Zhang 5 , John Carroll 5 , Jessica Stringer 5 , Mai Truong 6 , David Gardner 6 , Patrick Western 1 2
  1. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
  3. School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
  4. Bioinformatics and Computational Genetics, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  5. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  6. School of BioSciences, Melbourne University, Melbourne, Victoria, Australia

Epigenetic modifications facilitate cell differentiation partly by regulating transcription of developmental genes. While it has been proposed that epigenetic programming of germ cells is critical for offspring development, the mechanisms are poorly understood. As extensive evidence suggests that environmental factors, including drugs or diet, can alter germline epigenetic programming, understanding these mechanisms is essential. Polycomb Repressive Complex 2 (PRC2), containing the core subunits EED, EZH1/2 and SUZ12, catalyses the repressive modification H3K27me3. We previously demonstrated that oocyte-specific deletion of Eed versus Ezh2 differentially impacts offspring growth, with Eed deletion resulting in postnatal overgrowth while Ezh2 deletion results in growth restriction. As PRC2 is frequently dysregulated in cancer, various EZH2 and EED inhibitors have been developed. To investigate how PRC2 inhibition may impact oocytes, we used our genetic mouse models to delete PRC2 function and examine how H3K27me3 is regulated in oocytes. We identified a key window of transient PRC2 activity that regulates establishment of H3K37me3 at developmentally important genes in growing oocytes. Eed deletion resulted in 93% loss of H3K27me3 and de-repressed 343 genes (DEGs) in fully-grown Germinal Vesicle (GV) oocytes. Importantly, many of these genes contained H3K27me3 in human GV oocytes suggesting this PRC2 activity is conserved in humans. Conversely, while Ezh2 deletion reduced H3K27me3 by 75%, only 34 DEGs were identified in GV oocytes. Together our work identifies differences in the relative contributions of EED versus EZH2 to oocyte epigenetic programming. Our findings suggest that EZH2 ablation may more mildly impact oocytes and may explain different outcomes observed in offspring from Eed-null and Ezh2-null oocytes. Understanding these processes is critical for determining epigenetic inheritance mechanisms, and how exposure to clinically relevant EZH2 or EED inhibiting drugs may impact on oocyte epigenetic programming, and subsequent health and development of the next generation.