Epigenetic programming in the developing germline can be altered by environmental influences, such as diet and drugs, and affect health in offspring. 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 histone 3, lysine 27 tri-methylation (H3K27me3), thereby repressing developmental genes in multiple tissues.
To determine whether PRC2 programming inherited impacts on brain development and behaviour, we deleted Eed only in growing mouse oocytes and analysed outcomes in offspring. Histological and immunofluorescent analyses of neurological markers in cortex were conducted in fetal and adult offspring, and extensive behavioural testing was conducted in adulthood.
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. Post-implantation offspring from Eed-null oocytes demonstrated a significant neurological developmental delay and altered cortical patterning, including increased numbers of neural progenitors and disrupted neuronal patterning. Reduced brain weights were also observed at birth compared to genetically identical controls (n=22-28, p<0.005). Remarkably, altered cortical patterning was sustained in adult offspring from Eed-null oocytes with reduced BRN2 positive late-born neurons in the cortical plate (n=5-7, p<0.001). Extensive behavioural testing revealed that offspring from oocytes lacking EED had object recognition memory impairment and a severely blunted response to the challenge drug methamphetamine (n=27-29, p<0.001).
These data provide novel evidence that EED-dependent epigenetic programming in oocytes plays an essential role in regulating non-genetically inherited impacts on brain development, including sustained effects on cortical patterning and behaviour in adult offspring. Moreover, as this work reveals a sustained role for EED in mediating non-genetic impacts on offspring neurogenesis, determining whether therapeutic EED-inhibiting drugs may also alter oocyte programming, and affect offspring neurodevelopment, cognition and/or behaviour should also be assessed.