A systems-level study of the role of epigenetics in mediating in utero environmental influences on genome function and transgenerational effects

Understanding why individuals are different, in terms of their personal traits or predisposition to diseases i.e. 'phenotypes', remains one of biology's biggest challenges. To date, most studies have focused on either genetic variation or environmental factors that operate after birth. However, recent evidence suggests that the intrauterine environment can also influence adult phenotypes. Furthermore, it has been speculated that subsequent generations can also be affected, that is, the inherited predisposition to certain phenotypes and diseases can result from environmental influences during the intrauterine development of the parents or grandparents. But what are the molecular mechanisms that underlie these phenomena, also known as developmental programming? The cells must retain a 'memory' of the intrauterine environment and several lines of evidence suggest that the memory resides in epigenetic modifications of the DNA. Epigenetic modifications, such as addition of methyl groups to the DNA, occur naturally and control the expression of genes. A number of recent small-scale studies have shown that an adverse intrauterine environment, such as the mother consuming inadequate protein during pregnancy, induces aberrant epigenetic changes (epimutations) in the foetus. These epimutations are propagated throughout the life of the individual, hence becoming the memory of the intrauterine environment, and eventually influencing phenotypic outcomes in the adult. It is important to note that epimutations do not change the DNA sequence - only the epigenetic state is changed. However, two of the most important questions about how epigenetic mechanisms mediate the effects of developmental programming remain unanswered: (i) Where in the genome do these epimutations occur (ii) Which of these epimutations are passed on to future generations? As a result of recent technological advances, that allow us to simultaneously study the all genes in a genome, we can now perform powerful experiments that can address these very important issues. For my study, I will be using cutting-edge experimental approaches that combine the use of model organisms and computational biology, to understand the effects of exposure to a low-protein (LP) intrauterine environment. The LP model has been shown to have wide-ranging physiological effects, and most importantly, it is relevant to human populations who consume low protein diets for economic or cultural reasons. This project will reveal important insights into the fundamental epigenetic mechanisms associated with developmental programming.

Understanding the determinants of phenotypic variation remains one of biology's principal challenges. In addition to genetic variation and post-natal environment, it is becoming clear that the in utero environment also influences adult phenotypes, a phenomenon also known as developmental programming. But what are the molecular mechanisms that underlie developmental programming? Several lines of evidence suggest that the 'memory' of the in utero environment resides in epigenetic modifications such as DNA methylation and histone modifications. These modifications are involved in many aspects of genome function, including regulation of transcription. A number of small-scale studies have shown that an adverse in utero environmental influence, such as low protein, induces aberrant epigenetic changes in the foetus. These changes are propagated throughout the life of the individual, influencing phenotypic outcomes in the adult. However, we are only beginning to understand how epigenetic mechanisms mediate the effects of developmental programming, and two of the most important questions remain unanswered: (i) What are the quantitative/qualitative changes in the epigenetic landscape as a result of developmental programming (ii) Are these changes transmitted to future generations? It is critical that we now aim to provide an unbiased systems-level understanding of the molecular events associated with developmental programming. I would like to use whole-genome, systems-based approaches to elucidate the epigenetic basis of developmental programming in a mouse model of maternal low protein (LP). The LP model has been extensively studied, as it is relevant to human populations who consume low protein diets for economic or cultural reasons, and shown to have wide-ranging physiological effects, including epigenetic perturbations. It is therefore a useful model for understanding some of the fundamental epigenetic mechanisms associated with developmental programming.