Assessing the influence of maternal nutrition-sensitive epigenetic signatures in the POMC and PAX-8 genes on health-related outcomes in offspring

A key challenge in nutritional epigenetics is to link early pregnancy exposures with offspring epigenetic alterations and later phenotype or health outcomes. Epigenetic processes such as DNA methylation can influence gene expression and the periconceptional period is a particularly sensitive developmental window for establishing DNA methylation patterns. In this respect metastable epialleles (MEs) are of particular interest since their distinctive methylation patterns suggest establishment in very early embryonic development that may be sensitive to environmental factors. Furthermore, ME methylation patterns are tissue-independent making them promising candidates for the study of epigenetic developmental programming in humans using easily accessible tissues such as blood. Using a candidate gene approach, the research presented in this thesis characterised how early periconceptional exposures influence DNA methylation at two MEs at the POMC (Proopiomelanocortin) and PAX8 (Paired Box 8) genes and how methylation levels at these genes are associated with phenotype. Seasonality in The Gambia is associated with profound changes in multiple environmental factors and POMC and PAX-8 methylation is associated with Gambian season of conception (SoC) and mothers’ early pregnancy nutrition. POMC is a key regulator of satiety and energy balance and POMC hypermethylation is associated with obesity. PAX-8 is a thyroid transcription factor implicated in thyroid gland development and differentiation, important processes for children’s growth and neurocognitive development. In a prospective, year-long study of seasonally-driven weight and adiposity changes in Gambian mothers and children, a number of key associations with POMC methylation were identified. Firstly, POMC methylation was higher in those conceived in the rainy season and associated with maternal periconceptional amino acid concentrations. Secondly, higher methylation at POMC was associated with lower amplitude of mothers’ fat mass index change across the year. Thirdly, for both mothers and children, there was no association between POMC methylation and measures of appetite or satiety. Using a recall by epigenotype study design in Gambian children, PAX8 hypermethylation was associated with lower free thyroxine (FT4, a thyroid hormone) and smaller thyroid volume. Furthermore, increased FT4 (still within the population reference range) was associated with lower fat mass and bone mineral density. PAX8 methylation was also associated with maternal periconceptional levels of key one carbon metabolites homocysteine, cysteine, B6 and B12. In summary, this research highlights important phenotypic associations with DNA methylation at two human MEs with potential implications for epigenetic programming, developmental biology, and public health. Our demonstration that mothers’ diet in early pregnancy influences offspring DNA methylation which in turn is associated with a particular phenotype, suggests that targeted dietary interventions that positively influence the offspring’s epigenome could play a role in improving health outcomes in future generations.