The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Determining the impacts of epigenetic modifying drugs on the female germline (#322)

Ellen Jarred 1 2 , Lexie Prokopuk 1 2 3 , Heidi Bildsoe 1 2 , Te-sha Tsai 1 2 , Jessica Stringer 4 , Qing-Hua Zhang 4 , John Carroll 4 , David Gardner 5 , Patrick Western 1 2
  1. Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
  3. Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
  4. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  5. School of BioSciences, Melbourne University, Melbourne, Victoria, Australia

Epigenetic modifications, including DNA methylation and histone modifications, regulate gene expression to facilitate the differentiation and maintenance of distinct cell lineages in multicellular organisms. Activity of the enzymes that mediate epigenetic modifications can be influenced by environmental factors such as drugs or diet. Polycomb Repressive Complex 2 (PRC2) is an essential epigenetic modifier that catalyses histone 3 lysine 27 trimethylation (H3K27me3) at developmental genes in many tissues, including the germline. Germ cells give rise to mature sperm and oocytes that transmit genetic and epigenetic information to offspring. Integrity of this information is critical as alterations in the germline epigenome can affect offspring development and health. Common dysregulation of epigenetic modifications in cancers has driven the development of drugs that inhibit epigenetic enzymes. For example, Tazemetostat inhibits EZH2, the catalytic component of PRC2, and is currently in phase I/II trials for treatment of tumours, including in patients of reproductive age. While epigenetic drugs have great therapeutic potential, they act systemically and may detrimentally affect the germline epigenome. Using genetic models that lack PRC2 function in the oocyte, we are examining how H3K27me3 establishment is regulated in the growing oocyte and determining how Tazemetostat depletion of H3K27me3 affects oocyte maturation, and offspring growth and development. We demonstrate that oocytes are enriched with H3K27me3 during their growth and that genetic deletion of PRC2 activity alters offspring growth and development. Consistent with this, de novo germline mutations result in Weaver or Cohen-Gibson Syndromes in humans, characterised by overgrowth, skeletal abnormalities and learning deficits. Moreover, treatment of adult female mice with Tazemetostat severely depleted H3K27me3 in mature oocytes, indicating that this drug will detrimentally affect offspring. This work aims to determine the impacts of epigenomic drugs on the germline epigenome and offspring in mice, and ultimately improve clinical guidelines for these drugs.