Epigenetic information transmitted by eggs and sperm is thought to affect offspring development, but the mechanisms involved are poorly understood. Determining the molecular basis for epigenetic inheritance is critical given that the germline activity of epigenetic modifying enzymes can be altered by environmental influences, such as diet and drugs, with subsequent impacts on inheritance.
Embryonic Ectoderm Development (EED) is a core component of Polycomb Repressive Complex 2 (PRC2), which is a highly conserved epigenetic regulator required in oocytes for growth and development in offspring. PRC2 catalyses tri-methylation of lysine 27 in histone 3 (H3K27me3), thereby repressing developmental genes in multiple tissues.
To determine the role of PRC2 in programming inherited impacts on brain development and behaviour, we deleted EED only in growing mouse oocytes and analysed outcomes in offspring. This model enabled the study of epigenetic inheritance through the production of genetically identical offspring from eggs that lacked EED-dependent epigenetic programming. Consistent with a role for EED-dependent maternal programming, oocytes lacking EED had severely depleted H3K27me3 and an extensive range of neurodevelopmental genes were de-repressed. Moreover, histological and immunofluorescence analyses of key neurological markers in the developing brain revealed significant neurological developmental delay in embryonic offspring from oocytes in which Eed was deleted. Additionally, these offspring had significantly reduced brain weight at birth compared to genetically identical controls (n=59, p<0.005), indicative of altered brain development, and current RNA sequencing of developing cortex is expected to identify pathways that are dysregulated. Extensive behavioural testing in adult mice revealed that offspring from oocytes lacking EED had a severely blunted response to the challenge drug methamphetamine, compared to genetically identical control offspring (n=113, main effect of drug: p<0.001).
These data provide evidence that EED-dependent epigenetic programming in the oocyte plays an essential role in regulating non-genetic inheritance of brain development and behaviour.