The functional requirement for epigenetic systems in development and disease

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Exposure to environmental factors e.g. tobacco smoke, chemicals, air pollutants and nutrition can adversely affect human health. This can result in alterations to ‘chemical tags’ which normally exist on our DNA. These tags correspond to 'epigenetic marks'(on top of DNA) that can act as a ‘barcode’ of DNA function by indicating if genes are in an active or silent barcode state. Variations in the barcode can represent environmental induced changes in gene expression that have downstream adverse effects on the way cells and tissues work. This may result in enhanced disease susceptibility, for example resulting in an increase in cancer incidence or be linked with premature ageing processes. In this project we will study the contribution of epigenetic marks in regulating gene expression. Embryonic stem cells (ESCs) are models for early mouse development that can be grown in a petri dish under different culture conditions that either promote their continuous regeneration or alternatively coax them to differentiate into specific tissue types such as neural tissue. Of great interest is that one the chemical tags, 5-methylcytosine (5mC), undergoes programmed changes that are indicative of differentiation state and gene expression profiles. We will study how the lack of key enzymes (DNA methyltransferases (Dnmts)), which are important in DNA methylation reprogramming, affects ESC differentiation. Using appropriate model systems, we will undertake a detailed analysis to determine how lack of the Dnmt enzymes alters the ability of cells to differentiate normally. We use high resolution molecular profiling and imaging techniques to gain a better understanding of the contribution of epigenetics to development and by implication disease states. These studies underpin the new development of powerful diagnostic tests for disease, provide new markers for monitoring environmental exposure and promote the development of novel therapeutic interventions.