Germ cells undergo the most extensive epigenetic reprogramming of any in vivo cell type, ultimately resulting in the establishment of specialized epigenetic information in oocytes and sperm. Some of this information is transmitted via the oocyte and sperm to the next generation, and disruption of this inherited epigenetic information can lead to developmental defects and disease in offspring. EED is an essential component of Polycomb Repressive Complex 2 (PRC2), which establishes the epigenetic modification H3K27me3 in all animals, including humans. We recently demonstrated that PRC2 and H3K27me3 regulate epigenetic programming in mouse germ cells, which is important for early embryo development. We have now developed a model for deleting Eed only from growing oocytes in mice, providing a unique opportunity to the study epigenetic inheritance in genetically identical offspring. Consistent with this, loss of EED function severely reduces H3K27me3 and results in a highly significant, epigenetically transmitted, overgrowth phenotype that persists in offspring into adult life. Similar overgrowth occurs in Weaver syndrome patients who arise from oocytes or sperm that carry de novo germline mutations in EED. These patients have skeletal defects and intellectual disability consistent with known functions of PRC2 in bone and brain development. Preliminary data using DEXA demonstrates an increase in bone mineral density in combination with changes to fat and muscle content in the offspring derived from Eed deficient oocytes. We have also observed a significant decrease in litter size which suggests that loss of Eed in oocytes may affect female fertility. To further dissect the mechanism(s) responsible for the offspring phenotype we plan to determine the role of EED in oocyte programming, preimplantation and on postnatal development in offspring, with focus on bone and brain development. This work will provide greater understanding of the relationship between germline epigenetic programming and the developmental origins of disease.