Oral Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Oocyte epigenetic programming influences neurodevelopment in offspring (128361)

Chloe Edwards-Lee 1 2 , Ellen Jarred 1 2 , Sigrid Petautschnig 1 2 , Emily Jaehne 3 , Zhipeng Qu 4 , David Gardner 5 , William Gibson 6 , David Adelson 4 , Maarten van den Buuse 3 , Patrick Western 1 2
  1. Centre for Endocrinology and 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 Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia
  4. Department of Molecular and Biomedical Sciences, School of Biological Sciences, University of Adelaide, Adelaide, Victoria, Australia
  5. School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
  6. Department of Medical Genetics, University of British Columbia and British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada

Epigenetic modifications strongly influence gene expression and are vital in maintaining long-term memory of cellular identity and function. As oocytes and sperm transmit both genetic and epigenetic information to offspring, appropriate regulation of epigenetic programming within the male and female germlines is critical for normal offspring development. Oocyte epigenetic programming is highly complex, involving a range of epigenetic modifiers which establish a specific distribution of DNA methylation and histone modifications during oogenesis. Polycomb Repressive Complex 2 (PRC2) is a broadly evolutionarily conserved epigenetic complex which catalyses Histone 3 Lysine 27 trimethylation (H3K27me3) in primary-secondary follicle oocytes. PRC2-dependent epigenetic programming in oocytes is critical for normal developmental outcomes in offspring, including growth, brain and skeletal development. Moreover, de novo germline mutations in EED, EZH2 and SUZ12 are associated with Cohen-Gibson, Weaver and Imagawa-Matsumoto syndromes in humans, and are characterised by overgrowth, altered skeletal patterning and intellectual disability, highlighting the importance of also understanding PRC2 function within the human germline. We recently demonstrated that PRC2-dependent programming is coordinated with other chromatin modifications and precedes DNA methylation, reflecting highly organised epigenetic programming in mouse oocytes. Using a mouse model which lacks PRC2-dependent epigenetic programming during oogenesis, we are examining how the oocyte epigenome is established and how PRC2 regulates maternal epigenetic inheritance. We show that offspring resulting from oocytes which lacked PRC2-dependent epigenetic programming have disrupted neurodevelopmental and behavioural outcomes through to adulthood, compared to isogenic offspring which had normal oocyte epigenetic programming. As the mechanisms for these altered developmental outcomes in offspring remain unclear, this work also aims to provide insight into the molecular mechanisms underlying PRC2-dependent epigenetic inheritance. This work is critical in understanding how changes to oocyte epigenetic programming can disrupt epigenetic memory and alter developmental outcomes in the next generation.