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The University of Southampton
Biological Sciences

Research project: Epigenetic mechanisms and the developmental origins of health and disease

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Epidemiological studies show that a poor intra-uterine environment induced by restricted maternal diet, placental insufficiency or endocrine factors induces a phenotype in the offspring which in humans is associated with increased risk of developing chronic non-communicable diseases such as cardiovascular disease and the metabolic syndrome in later life.

The incidence of non-communicable diseases (NCD) such as diabetes, cardiovascular disease and the metabolic syndrome has risen sharply over the last 20 years and has now reached epidemic proportions. Genome wide association studies have shown that fixed genomic variations can only explain a fraction of the variation in NCD risk within a population. There is however increasing evidence that the environment particularly early life environment can influence our future disease risk. In humans a poor intrauterine environment has been associated with an increased risk of a range of non communicable diseases in later life. The mechanism by which early life environment can influence future disease risk is beginning to be understood and may involve epigenetic processes. Epigenetic processes are defined as processes that induce stable changes in gene activity without a change in gene sequence. The major epigenetic processes being DNA methylation, histone modification and miRNAs. There is now growing evidence that a range of environmental factors including diet can alter the epigenome. The epigenome is most susceptible to change during the prenatal and neonatal periods. The understanding of the mechanism by which early life environment can alter the epigenome leading to long term changes in disease risk is now critical both for the identification of individuals at increased risk and the development of intervention strategies to combat the rapid rise in NCDs.

This has been termed ‘fetal programming’ or ‘phenotype induction’, and forms the basis of the developmental origins of health and disease concept. In animal models, restricted nutrition during pregnancy induces dyslipidaemia, obesity, hypertension, endothelial dysfunction, hyerinsulinaemia and hyperleptinaemia in the offspring.

We have shown, for the first time, that feeding pregnant rats a PR diet alters promoter methylation patterns in a gene-specific manner in the offspring. We found decreased methylation of the 5’ promoter region of the PPAR a (20% lower) and GR (23% lower) genes in the liver after weaning of the offspring from dams fed a PR diet during pregnancy Altered methylation of specific CpG dinucleotides which correspond to the binding sites of regulatory proteins suggests a mechanism by which changes in the epigenetic regulation of genes established during development determines changes in transcription response specific stimuli, and thus the capacity of the tissue to respond to metabolic challenge. Thus altered gene methylation may provide a causal mechanism to explain how maternal diet can induce stable changes in gene expression within the offspring and may represent a fundamental mechanism for altering the phenotype. We are currently investigating the mechanism by which maternal diet can alter the epigenetic regulation of genes within the offspring with particular emphasis on the role of 1 carbon metabolism and regulation the DNA methyl transferases.

Related research groups

Molecular and Cellular Biosciences
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