Chemical tags on DNA act like a dimmer switch for genes, and this project will map how those switches go wrong when key enzymes are missing. The problem is that environmental factors like tobacco smoke or poor diet can alter these epigenetic marks, potentially raising the risk of cancer or accelerating ageing. Scientists know the marks change, but they do not fully understand how the enzymes that create them—DNA methyltransferases—control normal development. This project uses mouse embryonic stem cells grown in a dish to watch what happens when those enzymes are absent, tracking how cells lose their ability to turn into specific tissues like neurons. This is fundamental science. It will not produce a new drug or diagnostic test tomorrow. But by revealing the precise molecular choreography of epigenetic reprogramming, it lays the groundwork for future tools: blood tests that detect early cancer from altered methylation patterns, biomarkers to monitor environmental exposure, or therapies that reset faulty epigenetic barcodes. Similar fundamental work on DNA methylation underpins today’s liquid biopsy tests for cancer.
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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.
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