Theme 2:
Gene–environment interactions in early life: Molecular and cellular mechanisms
Our focus in developmental research is rapidly shifting from simple observations of effector–outcome relationships to addressing underlying processes, in which epigenetic mechanisms appear central. Our contributions have allowed significant advances in conceptual thinking and new experimental paradigms. For example, we have found programming-induced epigenetic changes in the glucocorticoid system and in metabolic pathways in rat and human tissues. Furthermore, our studies of reversibility and amplification (see Theme 3) suggest that changes in these systems are central to the underlying phenomena. A central role for oxidant/antioxidant systems has also been suggested. We have also found epigenetic changes in placental tissues, which may constitute a primary site of origin for some programming effects.
These findings fit with those of others showing that developmental epigenetic change can be nutritionally, stress hormone or possibly oxidant mediated. We now need to consider the broad range of epigenetic changes induced, and are developing high-throughput approaches to study epigenetic processes more broadly in rat, sheep and human studies.
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Current projects
1. Oxidative stress and the regulation of embryonic development
This is an experimental project examining whether oxidative stress affects embryonic development, and the role of epigenetic modifications in this process. This project will provide novel insights into pathways of oxidative stress that impact on normal homeostasis in virtually all physiological systems, including those related to disease states including inflammation, diabetes and environmental stress.
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Project leader: Assoc Prof Mark Hampton ( Project team: Prof Christine Winterbourn, Dr Karina O'Connor, Dr Louise Paton |
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2. Pharmacology of epigenetics
This is an experimental project investigating how epigenetic alterations may underpin a number of human brain disorders. The project uses human cells and tissues in a cell culture system in order to investigate whether drugs can be used for the treatment of human disorders with an epigenetic basis. Previous studies by the team have focused on determining how DNA responds to epigenetic drugs in human cells and tissues, with a view to developing treatments to correct aberrant epigenetic states that are developmentally programmed or induced during adulthood. NRCGD funding has enabled the development of high content analysis tools, with which marked species differences in the actions of certain drugs have been uncovered.
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Project leader: Prof Mike Dragunow ( Project team: Natasha Coppitiers 't Wallant (PhD student), Amy Smith (PhD student), Dr Pritika Narayan |
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3. Fundamentals of epigenetics in human and livestock development
This is an experimental project that aims to investigate the molecular mechanisms that underlie the impact of environmental factors very early in life that lead to variation in human phenotypes. The project focuses on the understanding that during early egg and embryo development, there are significant changes in the epigenetic regulation of genes that impact on growth and development, with impacts that become apparent later in life.
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Project leader: Prof Ian Morison ( Project team: Aniruddha Chatterjee (PhD student) |
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