ESA-SRB-AOTA 2019

Defining the role of EED in the establishment of oocyte transcriptome and how it contributes to maternally inherited disease. (#46)

Tesha Tsai 1 2 , Heidi Bildsoe 1 2 , Ellen Jarred 1 2 , Stephen Pederson 3 , Mai Truong 4 , David Gardner 4 , David Adelson 3 , Patrick Western 1 2
  1. Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia
  2. Hudson Institute of Medical Research, Melbourne, Victoria, Australia
  3. Bioinformatics and Computational Genetics, School of Biological Sciences , University of Adelaide , Adelaide, South Australia , Australia
  4. School of BioSciences, University of Melbourne, Melbourne, Victoria , Australia

Germ cell development involves extensive epigenetic reprogramming and ultimately results in the establishment of highly specialised epigenetic information in oocytes and sperm, disruption of which can lead to disease in offspring. EED is an essential component of Polycomb Repressive Complex 2 (PRC2) that is involved in the establishment of epigenetic modification H3K27me3 in animals to maintain gene silencing during development. In humans, de novo EED mutations in the germline cause Weaver syndrome, which is a disease characterised by overgrowth phenotype associated with skeletal abnormality and intellectual disability. To investigate how EED epigenetically regulates transcription in oocytes and offspring development, we developed a mouse model to delete Eed specifically in growing oocytes. Our previous work showed that this mouse model results in overgrowth of offspring that is similar to Weaver syndrome. Here, we isolated fully grown germinal vesicle (GV)- stage oocytes with surrounded nucleolus chromatin configuration and performed RNA-seq. Transcriptome analysis showed that 245 out of 248 (99%) differentially expressed genes are de-repressed by Eed oocyte-specific deletion (>2-fold increase; FDR=0.05), demonstrating the importance of EED in gene repression in the oocyte. Gene enrichment analysis using Ingenuity Pathway Analysis and G:Profiler showed that these dysregulated genes are involved in key developmental processes including brain and skeletal development, consistent with characteristics of Weaver syndrome. To further investigate how loss of EED in the oocyte leads to disease, we are analysing offspring gene expression and development in blastocysts, brain and bone with a focus on target genes identified from RNA-seq in oocytes. One candidate is Zdbf2, a gene that is epigenetically modified during pre-implantation embryo development and regulates offspring growth. Our work will provide greater understanding of maternal epigenetic programming, and how environmental insults mediated by drugs and diet could impact offspring health.