Lightning Talk + Poster ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Loss of PRC2 in mouse oocytes results in genetic and epigenetic impacts on neurodevelopment in offspring (143828)

Chloe Edwards-Lee 1 2 , Ellen Jarred 1 2 , Sharon Li 3 4 , William Gibson 5 6 , Marnie Blewitt 7 8 , Quentin Gouil 3 4 , 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. Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
  4. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
  5. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  6. British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
  7. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  8. The University of Melbourne, Melbourne, Victoria, Australia

Background: Epigenetic modifications strongly influence gene expression and are vital in maintaining long-term memory of cellular identity. As oocytes transmit genetic and epigenetic information to offspring, appropriate regulation of epigenetic programming is critical for offspring development. Polycomb Repressive Complex 2 (PRC2) is an evolutionarily conserved epigenetic complex which catalyses Histone 3 Lysine 27 trimethylation (H3K27me3) in primary-secondary follicle oocytes(1). This work aims to provide insight into how PRC2-dependent oocyte epigenetic programming ensures normal offspring growth and brain development(2). Moreover, de novo germline mutations in PRC2 subunits are associated with Cohen-Gibson, Weaver and Imagawa-Matsumoto syndromes in humans, characterised by overgrowth and intellectual disability, highlighting the importance of also understanding PRC2 function within humans(3,4).

Methods: C57BL/6 female mice with Eed deleted specifically in growing oocytes were mated to genetically distinct CAST/Ei males to produce hybrid offspring. Phenotypic evaluation of offspring at a range of developmental stages included collection of fetal, placenta and brain weights and tissues for immunofluorescence and molecular analyses. Furthermore, we established neural stem cell lines (NSCs, n=4/sex/genotype) and performed detailed molecular characterisation.

Results: Fetal offspring from PRC2-deficient oocytes were initially lighter than controls but experienced placental hyperplasia and subsequent catch-up growth. Importantly, we observed a range of similarities and differences in hybrid compared to C57BL/6 offspring. Using both short-read Illumina and long-read Nanopore RNA sequencing and strain-specific single nucleotide polymorphisms to differentiate parental alleles, we revealed sex-specific gene expression changes due to EED heterozygosity. Nanopore DNA sequencing in NSCs explored DNA methylation differences due to EED loss in the mother’s oocyte and EED heterozygosity.

Conclusion: This work provides the first detailed phenotypic characterisation of hybrid offspring lacking PRC2-dependent epigenetic inheritance, revealing disrupted gene expression and developmental outcomes. These data also provide insight into how EED heterozygosity influences neurodevelopment, which may aid in understanding human conditions such as Cohen-Gibson syndrome.

  1. Jarred EG, Qu Z, Tsai T, Oberin R, Petautschnig S, Bildsoe H, et al. Transient Polycomb activity represses developmental genes in growing oocytes. Clin Epigenetics. 2022;14(1):183.
  2. Oberin R, Petautschnig S, Jarred EG, Qu Z, Tsai T, Youngson NA, et al. Fetal growth delay caused by loss of non-canonical imprinting is resolved late in pregnancy and culminates in offspring overgrowth. Elife. 2024;13:e81875.
  3. Cooney E, Bi W, Schlesinger AE, Vinson S, Potocki L. Novel EED mutation in patient with Weaver syndrome. American Journal of Medical Genetics Part A. 2017;173(2):541-5.
  4. Imagawa E, Higashimoto K, Sakai Y, Numakura C, Okamoto N, Matsunaga S, et al. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum Mutat. 2017;38(6):637-48.