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The role of DNA methylation on neuronal activity in health and disease


Department of Biology

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Dr D Goffin , Prof M Whittington No more applications being accepted Self-Funded PhD Students Only

About the Project

Despite identical genetic sequences, neurones are highly divergent with distinct locations, morphology, connectivity, electrophysiology and transcriptional profiles. The epigenome – the patterns of DNA methylation and histone modifications – is ultimately responsible for defining the identity, function and transcriptional architecture of these different cell types, as well as integrating environmental signals into long-lasting changes in gene expression. In particular, DNA methylation plays a fundamental role in modifying DNA-protein interactions, influencing transcriptional states, activity-dependent gene regulation, learning and memory and ageing. Consequently, these alterations in DNA methylation must be properly recognised by the cell.

A key player in the recognition of DNA methylation is Methyl-CpG Binding Protein 2 (MeCP2). Mutations within MeCP2 lead to the devastating autism spectrum disorder, Rett syndrome. However, the underlying molecular functions of MeCP2 are poorly understood. We therefore developed novel mouse models that recapitulate disease-associated mutations in MeCP2. We found that these mice manifest Rett syndrome-like phenotypes through a loss of MeCP2 binding to methylated DNA and a concomitant reduction in MeCP2 protein stability (Goffin et al, 2012). Additionally, we found that loss of MeCP2 function leads to alterations in neural circuit function in a cell type-dependent manner (Goffin et al, 2014).

This project will build on these findings and provide new insights into the mechanisms through which DNA methylation and its recognition by MeCP2 plays in regulating proper neuronal function. This project will employ cutting edge genetic and electrophysiological techniques and is ideal for students with an interest in mechanisms underpinning health and disease.

Funding Notes

This is a self-funded project. Applicants need to have adequate funds to meet the costs of a self-funded research project including tuition fees and living expenses for the duration of the research programme. Please see information on tuition fee costs, living expenses and funding opportunities.

References

Applications are welcome for either for a 1-year MSc by Research or for a 3-year PhD.
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