Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

PRC2 establishes H3K27me3 at developmental genes in growing oocytes and regulates offspring development rate (#131)

Ellen Jarred 1 2 , Tesha Tsai 1 2 , Ruby Oberin 1 2 , Sigrid Petautschnig 1 2 , Heidi Bildsoe 1 2 , Zhipeng Qu 3 , Stephen Pederson 3 , David Adelson 3 , Qinghua Zhang 4 , John Carroll 4 , Jessica Stringer 4 , Mai Truong 5 , David Gardner 5 , 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. Bioinformatics and Computational Genetics, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia
  4. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  5. School of BioSciences, Melbourne University, Melbourne, Victoria, Australia

Epigenetic modifications modulate 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 and health, 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) catalyses the epigenetic modification, H3K27me3, to repress developmental genes in many tissues. Using genetic mouse models to delete PRC2 function in the oocyte, we examined how H3K27me3 establishment is regulated in growing oocytes. We identified a key window of transient PRC2 activity that regulates establishment of H3K37me3 at developmentally important genes in growing oocytes. Oocyte-specific deletion of the essential PRC2 subunit, Eed, de-repressed 343 genes (DEGs), primarily involved in neurogenesis and development, 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. Comparison of the DEGs with classically and non-canonically imprinted genes strongly indicated that EED regulation of these DEGs in growing oocytes represents a novel function for PRC2 in regulating maternal inheritance. Consistent with this, post-implantation offspring from Eed-null oocytes were initially developmentally delayed but exhibited increased placental weights and catch-up growth ultimately resulting in post-natal overgrowth compared to genetically identical controls. Significantly, de novo germline mutations in human EED/EZH2 result in Cohen-Gibson/Weaver Syndromes, characterised by overgrowth, skeletal abnormalities and learning deficits. Our work identifies a novel link between EED-dependent oocyte epigenetic programming and offspring development and strongly indicates that this activity is conserved in human oocytes. Understanding these processes is critical for determining epigenetic inheritance, 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.