Epigenetic mechanisms underlying nutritional contributions to mental health and cognition

Abstract

DNA methylation is vital in numerous biological processes from development and growth to disease susceptibility. It regulates a diverse range of gene classes and is influenced by several environmental factors. Maternal diet is a powerful environmental influencer in the epigenome of a growing foetus and subsequently impacts its developmental and risk of disease. Folic acid is essential in the production of the universal methyl donor SAM and during the 1st trimester of pregnancy has been well characterised as an inhibitor of neural tube defects. We have shown previously that continued folic acid supplementation during the 2nd and 3rd trimesters of pregnancy appears to have beneficial effects on neurocognitive performance in children followed for up to 11 years.

In this thesis novel roles of folic acid supplementation on the epigenetic mechanisms of the mother and child are examined, as well as the correlation these have with improved childhood cognition. The samples were obtained from a randomised controlled trial of folic acid supplementation during the 2nd and 3rd trimesters of pregnancy (FASSTT). The first study assesses the patterns of DNA methylation distribution between the treatment and placebo groups. Genes associated with neuronal pathways were some of the most affected and two groups regulated by DNA methylation were uncovered. These groups displayed distinct patterns of methylation distribution between the promoter and gene body regions with sensitivity to folate. These data supports previous work as many higher-order brain function related genes were targeted by folic acid supplementation. In the second study an imprint gene regulator (ZFP57) was investigated, which was the top effected target from the FASSTT study. Here for the first time, that ZFP57’s alternative promoter methylation is shown to be controlled by a mQTL variant residing within the region. Altered DNA methylation of this CTCF binding DMR influences expression of all ZFP57 isoforms currently identified. Additional SNPs in linkage disequilibrium with this mQTL possibly work in cohesion to influence methylation of the region. In the third chapter the focus is switched to the mothers of the FASSTT study DNA methylation alterations as a result of not supplementing with folic acid during trimesters two and three of pregnancy are assessed. Neuronal-related genes, many with disease states, were the most affected. A group of genes that change specifically due to pregnancy have been highlighted here for the first time. This thesis provides a solid foundation for the role of folic acid during trimesters two and three of pregnancy and the epigenetic effects that accompany this in both the mother and child.

Thesis is embargoed until 30th April 2026.

Date of Award	Jun 2024
Original language	English
Supervisor	Helene Mc Nulty (Supervisor), Colum Walsh (Supervisor), Rachelle Irwin (Supervisor), Guoliang Xu (Supervisor), Helene Mc Nulty (Supervisor), Colum Walsh (Supervisor), Rachelle Irwin (Supervisor) & Guoliang Xu (Supervisor)