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MRC DiMeN Doctoral Training Partnership: From Live Cells to Single-molecules: Unravelling the interplay between 3D genomic structure and gene expression


Project Description

This studentship is focused on applying state-of-the-art single molecule imaging techniques to study the molecular basis of DNA condensation and its impact upon gene expression. You will be part of a new, multidisciplinary collaboration between the Dept. of Oncology and Metabolism and Dept. of Chemistry with close ties to the Sheffield Institute for Nucleic Acids (http://genome.sheffield.ac.uk/).

Human cells must pack ~2 metres of DNA in to a cell nucleus approximately 10μm in diameter. The DNA must be packaged yet, highly organised and accessible for gene expression, DNA replication and DNA repair machinery. The 3D organisation also changes over time in response to cell stimulation such as DNA damage or infections. Central to this organisation is the wrapping of DNA around histone proteins to form nucleosomes that can be packed (condensed) or unpacked to allow proteins to access the genome. An array of modifying enzymes regulate these processes.

We have recently identified NDP52/CALCOCO2 as a putative transcription regulator (1) and preliminary data shows that this protein decondenses nucleosomes. NDP52 is connected to the NF-kB inflammation pathway and we therefore believe the protein regulates the expression of pro-inflammation genes. Therefore, this protein is related to fundamental cellular processes critical to health and disease, however it’s mechanism of action remains unknown.

The goal of this project is to dissect the mechanism of DNA condensation by NDP52 through a combined cell biology and in vitro approach, identifying the roles of any interacting proteins, and therefore define the molecular mechanism underpinning this fundamental process.

You will use a “top-down” and “bottom-up” multidisciplinary approach to investigate DNA organisation. This will include fluorescence-lifetime and super-resolution imaging to investigate condensation in live cells. The imaging will be complemented with genomics (ChIP- and RNA-seq) studies to investigate the distribution of the protein on the genome and the effect upon global transcription levels. Using single-molecule FRET experiments (2) you will measure nucleosome remodelling in a minimalised reconstituted system with recombinant proteins, enabling both the highest resolution characterisation, and identification of critical components.

This studentship provides a unique opportunity to be trained across a range of cutting-edge biophysical techniques and apply them to a fundamental question on the molecular understanding of disease. We are looking for creative individuals capable of working across disciplines. The successful applicant will be based in the Toseland Lab (https://www.sheffield.ac.uk/oncology-metabolism/staff/christoseland), whilst also working in the Craggs lab (https://craggs-lab.com).

Given the interdisciplinary nature of the role, we encourage applications from a diverse range of scientific backgrounds e.g. biophysics, physics, chemistry, biochemistry, structural biology and biomedical sciences. Interested applicants should contact Dr Toseland or Dr Craggs to discuss the project:


Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs.
Includes:
- Stipend at national UKRI standard rate
- Tuition fees
- Research training and support grant (RTSG)
- Travel allowance

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Fili et al Nature Communications (2017) 8 1871

Hellenkamp et al Nature Methods (2018) 15 669

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