Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Embryonic Ectoderm Development (EED) is an essential component of Polycomb Repressive Complex 2 (PRC2), which catalyses Histone 3 Lysine 27 trimethylation to repress a range of developmental genes and regulate developmental patterning. PRC2 also regulates H3K27me3-dependent imprinting, loss of which leads to placental hyperplasia in mammalian offspring generated by somatic cell nuclear transfer (SCNT).
To determine the role of PRC2 in programming inherited impacts on offspring, we deleted EED only in growing mouse oocytes and analysed fetal growth, placental and pregnancy outcomes. Oocytes lacking EED had severely depleted H3K27me3 and widespread gene derepression, including Plac1, an X-linked gene essential for placental and embryonic development (n=4-6, P=6.7E-13; FDR=3.19E-09). Moreover, embryonic offspring from EED-deficient oocytes initially had low blastocyst cell counts and low mid-gestation body weights (n=15-38, p<0.0001), demonstrating growth restriction. However, this initial developmental delay was followed by striking late-gestational placental hyperplasia (n=32-68, ****P<0.0001), and subsequent rapid fetal catch-up growth and overgrowth demonstrated by increased body weights at birth suggesting a role for placental hyperplasia in remediating fetal growth restriction (n=32-68, p<0.0001). Remodelling of the placenta involved expansion of fetal and maternal tissues, including conspicuously increased glycogen enriched cells in the junctional zone (n=10, ****P<0.0001). Genome-wide analyses identified extensive transcriptional dysregulation in affected placentas, including imprinted and non-imprinted genes. Effects on pregnancy were evident through decreased litter size (n=12-29, p<0.0001) and increased gestational length in litters derived from oocytes lacking EED (n=7-13, p=0.0068).
Ultimately, this work reveals a critical role for EED in the oocyte for regulating fetal and placental growth and function in offspring via complex intrauterine mechanisms that are independent of genetic background. As early development can mediate effects that persist into adulthood, this model provides a novel paradigm for studying inherited impacts on offspring health and disease.