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.
The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.
Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.
Programme: PhD in Biomedical Science (3 years)
Start Date: 1st October 2022 (the student will be affiliated with the Department of Biology)
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