Amyotrophic Lateral Sclerosis (ALS) is an aggressive neurodegenerative disease with no effective therapy. The established genetic causes of ALS can only explain a small fraction of the observed disease phenotypes. This project will explore how newly uncovered disease mutations in non-coding regions of the genome contribute to ALS.
Large scale whole genome sequencing (WGS) in ALS patients has highlighted the importance of new mutations in non-coding enhancers. Enhancers are gene regulatory elements crucial for cell-lineage specific gene expression, and are transcribed into non-coding RNAs called enhancer RNAs (eRNAs). You will lead a project to investigate whether novel non-coding ALS mutations affect the structure of eRNAs, and whether this affects epigenetic chromatin modifications and gene expression to drive ALS disease progression.
The project will establish a new and exciting collaboration between two Wellcome Trust Funded groups at the University of Sheffield. The Bose Lab is at the forefront of efforts to uncover the molecular basis for eRNA function. The Cooper-Knock lab leads analysis of the non-coding genome for WGS consortium Project MinE (www.projectmine.com), enabling identification and analysis of rare genetic associations in ALS. The project therefore provides a unique opportunity to work in some of the newest and fastest moving fields in science: molecular mechanisms of non-coding RNAs and the contribution of non-coding disease mutations to complex diseases.
You will receive a broad, multidisciplinary training in functional genomics approaches. This will include techniques for both high-throughout (in-cell) and targeted (in vitro) determination of RNA structure; next-generation and Nanopore sequencing (ChIPseq, NETseq and long-read RNAseq); targeted genome and epigenome editing (CRISPR/CRISPRa/i). Importantly, the project offers a unique opportunity to link these experimental approaches at the bench to bioinformatics training, including development of new deep-learning models for predicting genetic variants in ALS. The work will provide a new understanding of one of the most relevant questions in biology, with broad implications for disease mechanisms in common human diseases.
You will be supervised by Dr Daniel Bose (Dept. of Molecular Biology and Biotechnology) and Dr Johnathan Cooper-Knock (Dept. of Neuroscience). You will join our collaborative, supportive and tight-knit research groups and wider communities with the SInFoNiA and SITraN research centres. You will also join an active, friendly and lively PhD student cohort at the University of Sheffield, which hosts regular social events alongside networking and career development opportunities. We are committed to supporting the career development of our students and encourage attendance at both International and UK meetings, conferences and training courses to develop your research skills and interests.
As an interdisciplinary project, we welcome applicants with a diverse range of scientific backgrounds e.g. cell biology, computational biology, neuroscience, biochemistry, biophysics, structural biology and biomedical sciences. Interested applicants should contact Dr Bose to discuss the project further ([email protected]
Dr Daniel Bose (www.bose-lab.org; https://twitter.com/danbose
Dr Johnathan Cooper-Knock (http://sitran.org/people/cooper-knock/
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/
Bose, D.A., Donahue, G., Reinberg, D., Shiekhattar, R., Bonasio, R., and Berger, S.L. (2017). RNA Binding to CBP Stimulates Histone Acetylation and Transcription. Cell 168, 135–149.e22.
Bose, D.A., and Berger, S.L. (2017). eRNA binding produces tailored CBP activity profiles to regulate gene expression. RNA Biol. 0, 1–5.
Cooper-Knock, J., Moll, T., Ramesh, T., Castelli, L., Beer, A., Robins, H., Fox, I., Niedermoser, I., Van Damme, P., Moisse, M., et al. (2019). Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis. Cell Rep. 26, 2298–2306.e5.