Genomic translocations are a hallmark of cancer. Their identification has led to improvements in diagnosis and outcome in haematological malignancies. We are particularly interested in leukaemias and lymphomas resulting from translocations in the immunoglobulin (Ig; antibody) locus in B lymphocytes. Normal rearrangement of Ig gene loci and their super-enhancers is needed to generate the antibody repertoire, but these super-enhancers can be aberrantly rearranged and “hijacked” by oncogenes. However, our understanding of this genomic information is very limited and therapeutic strategies exploiting this data are yet to be developed.
Over 70 genes are translocated to the Ig loci and overexpressed as a result of the rearrangement, but this is not a random process. Recurrent translocations imply a common mechanism that supports developmental stage-specific, long-range interactions between particular promoters and enhancers. A strong candidate mechanism would be shared transcriptional regulatory proteins (TRPs) that might bind regulatory regions at each locus, favouring the translocation.
This PhD aims to:
- Use artificial intelligence (AI) to mine epigenomic datasets to identify TRPs that bind Ig and partner gene enhancers and promoters.
- Use public and in-house chromosome conformation data to connect enhancers with gene promoters by developing maps of promoter-enhancer interactions.
- Identify TRPs actually bound to enhancer and promoter regions by CAS9 driven immunoprecipitation and mass spectrometry.
By combining experimental work and bioinformatics training, the student will develop both expertise and knowledge relating to how translocations lead to oncogenic expression and transferable skills in the integrative analysis of complex types of quantitative data. This training will be underpinned by a supervisory team with the following expertise:
- Experimental analysis of B-cell leukaemia: Lisa Russell - https://www.ncl.ac.uk/nicr/staff/profile/lisarussell.html
- Computational genomics: Daniel Rico - https://www.ncl.ac.uk/icm/people/profile/danielrico.html
- Immune system development: Sophie Hambleton - https://www.ncl.ac.uk/icm/people/profile/sophiehambleton.html
- Chromatin regulation of immunoglobulin loci: Anne Corcoran - https://www.babraham.ac.uk/our-research/lymphocyte/anne-corcoran
Benefits of being in the DiMeN DTP
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/
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 2019.
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
Original source and application process https://www.findaphd.com/search/ProjectDetails.aspx?PJID=103814