Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour

Background: Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but as yet there is little direct evidence for such mechanisms in humans. Method: We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing. Results: Within the UK Southampton Women’s Survey (SWS) we first which identified 41 differentially methylated regions of interest (DMROI) at birth associated with child’s full-scale IQ at age 4-years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS seven-year olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n=108). Here, HES1 DMROI methylation predicted differences in early infant behavior, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site. Conclusions: Thus, our findings suggest that perinatal epigenetic processes mark later neuro-cognitive function and behavior, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.