Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Setting a foundation for future offspring:  Polycomb-dependent epigenetic programming in the maternal germline (#11)

Patrick Western 1 2 , Sigrid Petautschnig 1 2 , Ruby Oberin 1 2 , Ellen Jarred 1 2 , Zhipeng Qu 3 , Neil Youngson 1 2 4 , Tesha Tsai 1 2 , Rheannon Blucher 1 2 , Heidi Bildsoe 1 5 , Steven Peterson 3 , Mai Truong 6 , Narelle McGregor 7 , Emily Jaehne 8 , Qing-hua Zhang 9 , Jessica Stringer 9 , William Gibson 10 , John Carroll 9 , David Gardner 6 , Maarten van den Buuse 8 , Natalie Sims 7 , David Adelson 3
  1. Department of Molecular and Translational Science, Monash University, Clayton, Vic, Australia
  2. Centre for Reproductive Health, Hudson Institute for Medical Research, Clayton, VIC, Australia
  3. Department of Bioinformatics and Computational Genetics, School of Biological Sciences, Adelaide University, Adelaide, SA, Australia
  4. School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia
  5. Centre for Reproductive Health, Hudson Institute for Medical Research, Clayton, Victoria, Australia
  6. School of BioSciences, University of Melbourne, Melbourne, VIC, Australia
  7. Bone Cell Biology and Disease Unit, St Vincent’s Institute of Medical Research, Melbourne, Vic, Australia
  8. School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia
  9. Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  10. Department of Medical Genetics, University of British Columbia and British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada

Epigenetic modifications modulate cell differentiation partly by regulating transcription of developmental genes. While epigenetic programming in germ cells may be altered by environmental influences and affect offspring development, the mechanisms are poorly understood. Polycomb Repressive Complex 2 (PRC2) catalyses the epigenetic modification, H3K27me3 to repress developmental genes in many tissues. We demonstrated that transient PRC2 activity regulates establishment of H3K37me3 at developmentally important genes in growing oocytes. Loss of PRC2 in growing oocytes de-repressed 343 genes involved in development, neurogenesis, chondrogenesis and tissue patterning suggesting that PRC2 epigenetically regulates genes important for offspring development. Many of these genes contained H3K27me3 in human GV oocytes, demonstrating that PRC2 activity is conserved in human oocytes. Consistent with a role for PRC2 in maternal inheritance, post-implantation mouse fetal offspring from oocytes lacking PRC2 were developmentally delayed, but exhibited placental hyperplasia, accelerated growth late in fetal life, extended gestation and perinatal overgrowth, compared to genetically identical controls. Placental transcription and DNA methylation was significantly altered, including increased expression of the H3K27me3 imprinted gene and amino acid transporter, Slc38a4. While placentas contained increased numbers of glycogen enriched cells, late gestation fetal glucose levels were lower, but the fetal circulating metabolic profile was similar to controls. Fetal development was significantly affected as demonstrated by altered bone and brain development, and behaviour, in offspring. 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 link between PRC2-dependent oocyte epigenetic programming and offspring development and indicates that this activity is conserved in human oocytes. Understanding these processes is critical for determining how epigenetic programming in oocytes regulates health and development of the next generation and how environmental influences, such as drugs or diet, could alter non-genetic inheritance in mammals.