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The University of Southampton
Biological Sciences

Research project: Identification of perinatal epigenetic markers of later phenotype

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The incidence of obesity has risen sharply over the last 20 years and has now reached epidemic proportions, with more than 1 billion adults overweight and 300 million adults clinically obese worldwide.

Genetic variation in a number of genes have been linked to obesity, although to date single nucleotide polymorphisms and copy number variations explain only a fraction of the risk of obesity and metabolic disease in humans. However, there is now substantial evidence from both human and animal studies that the quality of early life environment before and after birth can affect susceptibility to adiposity and metabolic disease in later life. Epigenetic regulation of gene function has been suggested as one mechanism by which early life environmental factors can induce persistent phenotypic changes. Epigenetic processes such as DNA methylation induce heritable changes in gene expression without a change in nucleotide sequence. Epigenetic regulation is central to the control of gene expression, regulating genomic imprinting, X chromosome inactivation, and cell specification. Epigenetic processes have also been implicated in the process of developmental plasticity; the mechanism by which an organism adjusts its developmental trajectory in response to environmental cues with long term effects on gene expression and phenotype.. Persistent epigenetic and phenotypic changes in the offspring have been shown to be induced by maternal global dietary restriction, folic acid supplementation, neonatal over feeding[], constrained intrauterine blood supply and maternal behavior. There is also evidence that a similar mechanism may operate in humans, as differences in the methylation of a number of imprinted and non-imprinted genes have been found in the peripheral blood leukocytes of individuals whose mothers were exposed to famine during pregnancy. We have also shown that that the methylation of a CpG site within the promoter of the RXRA gene in umbilical cord at birth predicted greater than 25% of the variation in %fat mass in children aged 6 and 9 years. This supports the paradigm that developmentally induced epigenetic marks make a significant contribution to later phenotype and suggests that the detection of such marks even in peripheral tissues may provide useful predictive markers of later phenotype in more disease relevant cell types.

As the identification of such markers would be extremely valuable for assessing individuals at risk of future non-communicable disease and may allow the identification of novel pathways that influence the development of later, we have carried out the first systematic genome wide screen to identify differences in DNA methylation levels in umbilical cord tissue collected at birth, associated with child’s adiposity at age 6 years. Validation of these epigenetic predictive markers is currently underway to determine their utility as biomarkers and role in the development of adiposity.

Funding: Epigen Consortium 2010-2015

Related research groups

Molecular and Cellular Biosciences
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