Elucidation of the molecular mechanisms by which in utero environment influences adult onset phenotypes and diseases in humans.

he developmental programming hypothesis posits that environmental insults in utero can have a major influence on adult-onset disease and phenotypic outcomes. We are interested in understanding the mechanistic basis of this phenomenon in mammals. In particular, identifying developmental programming-induced molecular perturbations, such as epigenetic marks, and then understanding how these perturbations influence phenotype. The project will be highly inter- disciplinary and will involve novel in vitro assays, followed by translation into a unique long-standing human cohort from the Gambia. The experimental work will be underpinned by bioinformatics/statistical analyses of (epi)genome-scale datasets.

Developmental programming is the process by which the in utero environment influences phenotypic and disease outcomes in post-natal life. There is currently great interest in identifying the molecular mechanisms that underlie developmental programming, and modulation of epigenetic marks (e.g. DNA methylation) has emerged as potentially a key contributing factor. We recently analysed a mouse model in which pregnant females are exposed to a low protein (LP) diet and their offspring subjected to phenotypic and DNA methylation analyses when they reach adulthood (Holland et al 2016, Science). We found that in the LP-exposed offspring, body weight is linearly correlated with methylation dynamics at ribosomal DNA. Strikingly, the methylation response in these animals was also influenced by previously unappreciated genetic variation within the rDNA. Similar effects were also found in developmental programming models of high fat and obesogenic diet. Given the ubiquity of rDNA in all life forms, we propose that such gene- environment induced epigenetic dynamics also occur in humans. In this regard, we have a long- term study on a population in rural Gambia, wherein seasonal variations in food supply and metabolic demand provide a natural experiment by which to study the effect of periconceptional environment (including maternal nutritional status) on epigenetic development in the offspring. The PhD project will involve first developing an in vitro assay for identifying environmentally- responsive rDNA variants in humans. These will then be studied mechanistically in vitro, and also translated into The Gambian cohort. The work will also entail generation and bioinformatic analysis of (epi)genome-scale datasets. There will also be opportunities to visit The MRC center in The Gambia. Overall, the project will aim to deliver a molecular understanding of the in utero basis of complex diseases and phenotypes in mammals, and is best suited to candidates interested in developing both wet-lab and computational skills.