Paediatrics (RCH) - Theses
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ItemInfluence of maternal diet and lifestyle on twins DNA methylation at birth and the changes that occur within the first 18 months of life( 2013)The Developmental Origins of Heath and Disease (DOHaD) concept describes the importance and impact of prenatal environment on later health and disease risk. One of the mechanisms of how prenatal environment can influence the development of the offspring is epigenetics, defined as the study of mitotically and/or meiotically heritable changes in the gene function independent of DNA sequence. The term “epigenetics” was coined by Conrad Waddington as an important mechanism that shapes the development of an organism. In this PhD, DNA methylation was used as a representative of epigenetic status, as it is the most robust epigenetic mark. There is mounting evidence for associations between maternal factors and DNA methylation at gene-specific, global, and genome-wide levels. However, most studies to date have been limited in scope, examining DNA methylation in specific regions in one or two cell types. Newborn twins’ samples from the Peri/postnatal Epigenetic Twins Study (PETS) cohort were used for all analyses in this thesis. The benefit of using twins is the ability to investigate shared and non-shared maternal factors (e.g., the fetal ‘supply line’) on DNA methylation, which until now, have not been studied. The major aim of my PhD was to investigate associations of various shared and non-shared maternal factors with DNA methylation at a gene-specific (Chapter 3 and 4), global (Chapter 4) and genome-wide level (Chapter 5) in various cell types. At a gene-specific level, IGF2 and H19 were the chosen as candidate genes because they are known to be important in embryonic growth. Repeat elements Alu and LINE-1 were used as surrogates of global methylation. Epigenetic profile was hypothesised to be dynamic in the first few months of life, due to its critical developmental stages in early childhood. Previous studies have used a cross-sectional model to investigate DNA methylation changes over time at various ages, but very few studies have used a longitudinal model for this purpose from birth to infancy. My PhD also aimed to fill this gap by using a longitudinal study of methylation in twins from birth to 18 months of age at a genome-wide level (Chapter 6). Using the Sequenom MassARRAY EpiTYPER platform to measure DNA methylation of genomic regions controlling expression at IGF2/H19, and in the Alu and LINE-1 interspersed repeats in five different cell types of newborn twins, it was found that both shared and non-shared maternal factors associate with DNA methylation at birth, and often in a cell type- and region-specific manner, even with the surrogates of global methylation. These are valuable findings, as they further inform that associations of specific maternal factors with certain regions and cell types cannot always be extrapolated to other regions or cell types. This study further reports that false positives can occur, most likely due to small sample size. Methylation analysis at a genome-wide level found that maternal factors were more likely to influence genes involved in metabolic pathways, especially amino acid metabolism. It was also found that maternal factors were less likely to affect regions of functional importance. These findings are important for future studies of prenatal environment. Finally, it was reported that one third of the genome in buccal epithelium rapidly changes over time in the first 18 months of life. This study has revealed the complexity of the epigenome in the newborn in response to the influence of maternal factors, and the dynamic changes over time in the epigenome from birth to infancy. Validation of associations in larger sample sizes in various cell types, and identification of the legacy of such influences in the long-term health of the offspring warrant further investigation. Furthermore, expression analysis on these findings would further solidify the clinical relevance of the associations seen.