Epigenetic modifications are essential in regulating embryonic and placental development. However, the molecular basis through which epigenetic information is inherited from parents to offspring and the impacts this information has on placentation and pregnancy remains poorly understood.
Embryonic Ectoderm Development (EED) is an essential component of Polycomb Repressive Complex 2 (PRC2), a highly conserved epigenetic regulator required in oocytes for offspring growth and development. PRC2 catalyses tri-methylation of histone 3 lysine 27 (H3K27me3), thereby repressing developmental genes in multiple tissues. PRC2 is an important epigenetic modifier of placentation, with disruption of its subunits linked to placenta-associated disorders.
To determine the role of PRC2 in programming inherited impacts on placentation, we deleted EED only in growing mouse oocytes and analysed 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 oocytes lacking EED initially demonstrated significant embryonic growth restriction (n=15-38, p<0.0001), followed by catch-up growth. Placentas from these offspring were initially similar in weight to genetically identical but epigenetically different controls but became significantly larger in mid-late gestation (n=32-68, p<0.0001). Histological analyses of E17.5 placenta from EED deficient oocytes showed an expanded junctional zone with abnormal projections of spongiotrophoblast into the labyrinth. Effects on pregnancy were also 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). Current RNA sequencing is expected to identify pathways involved, providing insight into the mechanisms regulated by EED-dependent maternal inheritance.
Together, these data provide evidence that EED-dependent epigenetic programming in the oocyte plays an essential role in regulating placental development and pregnancy. Further defining this, and similar mechanisms, will provide insight into how altered epigenetic inheritance affects placental function and offspring development.