Association between perinatal methylation of the neuronal differentiation regulatorHES1and later childhood neurocognitive function and behaviour

Abstract

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 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 7-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 behaviour, 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 neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…We used placental DNA in our analysis, and studies that utilize available tissue from the offspring (cord blood, umbilical cord, buccal cells) would provide additional information as to mechanisms accounting for offspring disease risk. 45 Our study included relatively low numbers of women who smoked and this means that although we were able to identify smoking as a confounder for IGF2 expression, we were not powered to undertake formal testing of mediation. We did not have access to placental weights for this study, which would have been useful for further analysis of any relationship between placenta weight, gene expression, and DNA methylation.…”

Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes

“…This association was adjusted for potential confounding by maternal IQ, birth weight and maternal smoking. The positive association between HES1 methylation and child cognitive development was validated in a further 200 cord blood samples from the Southampton Women’s Survey cohort, where more specific child cognitive functions were assessed at age seven years, including cognitive flexibility, executive function and memory [36]. This association between HES1 methylation and neurodevelopment extends to child behavioral outcomes.…”

“…Such insights have been gained from large birth cohort studies, where whole genome methylation analyses of cord blood at birth has been assessed with respect to the child’s later cognitive and behavioral outcomes. For example, in the Southampton Women’s Survey, child IQ at four years was positively associated with cord blood methylation of two CpG loci in HES1 , a gene that encodes a transcription factor involved in neuronal cell proliferation and differentiation, and in diencephalon development [36]. This association was adjusted for potential confounding by maternal IQ, birth weight and maternal smoking.…”

“…This association between HES1 methylation and neurodevelopment extends to child behavioral outcomes. In one-year-old children from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort, lower externalizing behavior scores were also associated with greater cord blood HES1 methylation [36]. These studies conducted in large cohorts highlight the potential for genome wide DNA methylation studies to identify biomarkers of early neurodevelopmental outcome (Table 1).…”

Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

“…The downstream effects of DNA methylation marks associated with disease are important context for this. For instance, DNA methylation changes future science group www.futuremedicine.com may change chromatin state and binding of transcription factors [50] and consequent changes in transcript and protein levels [51]. These may happen in only one cell subtype, or in more than one cell type and they may also be causative to changes in cell fate.…”