About the Project
About the UK Dementia Research Institute
There are currently around 850,000 people with dementia in the UK. This is projected to rise to 1.6 million by 2040. The UK DRI at Imperial has been established to address a medical research area of the highest importance and future impact. As one of seven national centres of excellence embedded in major UK universities, we intend to transform the diagnosis, treatment and care of people with dementias. The Medical Research Council and charity partners the Alzheimer’s Society and Alzheimer’s Research UK have invested £290m in fulfilment of the ambition identified in the Prime Minister’s 2020 Challenge on Dementia.
About the Laboratory
The programme of Dr Alexi Nott is focused on understanding how the epigenome and chromatin architecture regulates cell type gene expression programmes in the healthy brain and during ageing and disease. We are approaching this challenge using next-generation sequencing of patient-derived brain tissue and stem cell-derived models of disease.
Ageing is the highest risk factor for dementia, creating a major health crisis as the ageing population expands to one in five people in the UK by 2030. Genetic variants that increase the risk of ageing-associated diseases such as Parkinson’s disease and Alzheimer’s disease have been identified. The function of these disease-risk variants is largely unknown. They often reside outside of genes in DNA regions thought to regulate gene expression, called enhancers. Enhancers integrate environmental signals, resulting in gene expression programs that guide cell type-specific responses. The colocalization of disease-risk variants in enhancers suggest that enhancer function is critical for normal ageing and that enhancer dysfunction is a driver of disease. While enhancers are key for inferring cell type-specific gene expression programs, prior work has focused on bulk tissue, potentially masking epigenomic changes that occur in rare cell types. For example, microglia, the immune cells of the brain, have been implicated in ageing-associated disorders; however, they constitute only 5% of cells in the brain and have been difficult to detect by bulk tissue analysis.
This PhD project is focused on understanding how cell type-specific enhancer function drives brain physiology and ageing-related disease. We will utilize nuclei isolation approaches developed for the brain to examine the epigenome of cell types and cell states implicated in disease. Tissue will be utilized from postmortem brain banks and resected tissue archives. The candidate will use next-generation sequencing approaches, such as chromatin immunoprecipitation sequencing (ChIP-seq), CUT&Tag and ATAC-seq to identify cell type specific gene regulatory regions. Genome conformation assays will be used to identify the gene targets for these noncoding regulatory regions. Integrative analysis with publicly available genetic data will be used to identify potential disease-relevant regions. Select gene regulatory regions implicated in disease may be tested using iPSC-derived models of brain cell types together with CRISPR-mediated DNA editing. The ultimate goal of this project is to reveal cell type-specific gene networks and transcription factors important for brain ageing and highlight candidate targets that are dysregulated in disease. To facilitate scientific growth, PhD students will be given opportunities to work closely with a broad range of other scientists across the UK DRI and in external universities.
For informal enquiries please contact Alexi Nott ([Email Address Removed]).
For application, please send a full CV, stating your motivation for applying, your nationality, and the full contact details of two academic referees to [Email Address Removed]
We regret that due to the large volume of applications received, we are only able to notify those shortlisted for interview. Applications will be considered until the position is filled.
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