Fetal germ cells are the precursors of oocytes and sperm, which transmit an individual’s genetic and epigenetic information to the offspring. During fetal germ cell development, epigenetic information is reprogrammed/erased to allow the establishment of new sex specific information required for development in the next generation. However, the function of histone modifications in the germline and subsequent offspring development are poorly understood.
Polycomb repressive complex 2 (PRC2) establishes trimethylation of lysine 27 of histone 3 (H3K27me3), which is critical for regulating developmental gene expression. Therefore, we hypothesise that PRC2 regulates epigenetic programming in the germline with consequent impacts on offspring growth and development.
Immunofluorescence and super-resolution imaging were used to determine the spatio-temporal profiles of PRC2 and H3K27me3 during epigenetic reprogramming and mouse germ cell development. In addition, complementary genetic and pharmacological models were used to investigate the impacts of depleting PRC2 function on: 1) fetal germline reprogramming; 2) oocyte development; 3) and maternal offspring growth.
Immunofluorescence revealed striking remodelling of H3K27me3 in the germ cell nucleus specifically during epigenetic reprogramming. This histone relocalisation co-incided with transient expression of PRC2. Pharmacological blockage of PRC2 demonstrated an essential function for PRC2 in this remodelling. In addition, oocyte specific deletion of an essential PRC2 component (Eed) demonstrated that PRC2/EED is required for oocyte enrichment of H3K27me3 and resulted in delivery of pups that were significantly heavier than age-matched controls.
Together our data indicate that PRC2 regulates the critical epigenetic modification H3K27me3 at key stages of germline development and oogenesis and reveal an important role for PRC2/EED in offspring growth. Moreover, oocyte specific deletion of PRC2 provides a significant model for studying the impacts of epigenetic patterning in the maternal germline and their consequences for offspring development and health in the absence of confounding factors.