Loss of EED in the oocyte causes initial fetal growth restriction followed by placental hyperplasia and offspring overgrowth

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to placental hyperplasia in mammalian offspring generated by somatic cell nuclear transfer (SCNT). In this study, we show that offspring from mouse oocytes lacking the Polycomb protein Embryonic Ectoderm Development (EED) were initially growth restricted, characterised by low blastocyst cell counts and substantial mid-gestational developmental delay. However, this initial delay was remediated by striking late-gestational placental hyperplasia, closely followed by rapid fetal catch-up growth and subsequent overgrowth. Remodelling of the placenta involved expansion of fetal and maternal tissues, including conspicuous expansion of the glycogen enriched cell population in the junctional zone. Genome-wide analyses identified extensive transcriptional dysregulation in affected placentas, including a range of imprinted and non-imprinted genes. Our data demonstrate that altered PRC2-dependent programming in the oocyte elicits complex program of fetal growth restriction followed by placental hyperplasia, which drives catchup growth that ultimately results in perinatal offspring overgrowth.