Oral Presentation 43rd Lorne Genome Conference 2022

PRC2 establishes H3K27me3 at developmental genes in growing oocytes and regulates offspring development via a genetically independent mechanism (#25)

Ellen Jarred 1 2 , Ruby Oberin 1 2 , Sigrid Petautsching 1 2 , Zhipeng Qu 3 , Tesha Tsai 4 , Heidi Bildscoe 1 , Stephen Pederson 3 , Thi Truong 5 , Narelle McGregor 6 , Emily Jaehne 7 , Qing-hua Zhang 8 , Jessica Stringer 8 , John Carroll 8 , David Gardner 5 , Maarten van den Buuse 7 , Natalie Sims 6 , David Adelson 3 , Patrick Western 1 2
  1. Centre for Reproductive Health, Hudson Institute for Medical Research, Clayton, Vic, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Vic, Australia
  3. Department of Bioinformatics and Computational Genetics, School of Biological Sciences, Adelaide University, Adelaide, SA, Australia
  4. School of Health and Biomedical Sciences , RMIT University, Bundoora, Vic, Australia
  5. School of BioSciences, University of Melbourne, Melbourne, Vic, Australia
  6. Bone Cell Biology and Disease Unit, St Vincent’s Institute of Medical Research, Melbourne, Vic, Australia
  7. School of Psychology and Public Health, La Trobe University, Bundoora, Vic, Australia
  8. Biomedicine Discovery Institute, Monash University, Clayton, Vic, Australia

Epigenetic modifications modulate differentiation and cell identity by regulating developmental gene transcription. While it has been proposed that germline epigenetic programming is critical for offspring development, and may be altered by environmental influences, the mechanisms are poorly understood. Polycomb Repressive Complex 2 (PRC2) catalyses the epigenetic modification, H3K27me3, repressing developmental genes in many tissues. We have identified a 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) in fully grown oocytes. These DEGs were primarily involved in development, including neurogenesis, bone development and tissue patterning. Importantly, many of these genes contained H3K27me3 in human oocytes, suggesting PRC2 activity is conserved in humans. The DEGs identified were largely distinct from classically and non-canonically imprinted genes, strongly indicating that regulation of these DEGs represents a novel function for PRC2 in oocytes and potentially inheritance. Consistent with this, compared to genetically identical controls, post-implantation fetal offspring from Eed-null oocytes were developmentally delayed but exhibited increased placental weights and catch-up growth ultimately resulting in post-natal overgrowth. Moreover, these offspring had altered bone and brain development, and behaviour. While a range of Eed-dependent oocyte DEGs were altered in offspring bone and brain, the majority did not overlap with imprinted genes. These outcomes are reminiscent of Cohen-Gibson/Weaver Syndromes caused by de novo germline mutations in human EED/EZH2 and characterised by overgrowth, skeletal abnormalities and learning deficits. Our work identifies a novel link between EED-dependent oocyte epigenetic programming and offspring development, and 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.