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EASTBIO Exploiting functional fragility in parasitic nematode gene expression: using genome editing and transcriptome analysis to investigate the genome-wide impacts of spliced leader trans-splicing


School of Medicine, Medical Sciences & Nutrition

Dr B Mueller , Dr J Pettitt , Dr M Wenzel , Prof I Stansfield Wednesday, January 06, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Dr Berndt Mueller (University of Aberdeen)
https://www.aberdeenwormlab.org/

Dr Jonathan Pettitt (University of Aberdeen)
https://www.aberdeenwormlab.org/

Dr Marius Wenzel (University of Aberdeen)
https://www.abdn.ac.uk/people/marius.wenzel

Professor Ian Stansfield (University of Aberdeen)
https://www.abdn.ac.uk/people/i.stansfield

Nematode parasites impose a significant global human health burden and also jeopardise food security and economic sustainability through their impacts upon both plant and animal agriculture. Controlling parasitic nematodes remains a major issue. There are only few classes of drugs to treat animal and human parasitic nematodes and resistance to existing therapeutics is a growing challenge. Similarly, control of plant parasitic nematodes is frequently reliant upon harsh soil treatments, which are environmentally damaging. There is thus a pressing need to develop new, broad-specificity drug treatments.

Nematode gene expression is highly unusual because many genes are arranged in operons (polycistrons) that are controlled by a single promotor. Pre-mRNA transcribed from these operons must be processed by ‘spliced leader trans-splicing’, which resolves the polycistronic RNA into individual transcripts for translation. Research in the Aberdeen Worm Lab is directed towards understanding the molecular machinery the directs these RNA processing events, using C. elegans as a model nematode. We have identified a series of nematode-specific drug targets, the inhibition of which is predicted to lead to impaired development and reproduction by perturbation of RNA processing.

This multidisciplinary project aims to understand the molecular effects of inhibiting spliced leader trans-splicing using genome editing and high-throughput transcriptome surveys. The student will work with wild-type and CRISPR genome-engineered mutant C. elegans strains using the auxin-degron system to deplete components of the nematode-specific RNA processing machinery. Transcriptome-wide changes in gene expression and splicing patterns will be identified using full-length isoform sequencing on the Oxford NanoPore MinION sequencing platform. Global analysis of changes in spliced leader trans-splicing events will be examined using in-house computational analysis pipelines, with scope for developing novel bioinformatics methods. Thus, by characterising the global post-transcriptional effects of individual molecular components, the project will allow us to refine our focus on drug development strategies that are likely to have most impact on nematode gene expression.

This is a unique and exciting opportunity to gain multidisciplinary training in state-of-the-art model organism-based gene function analysis and gene editing, combined with computational biology (including recently developed high-throughput sequencing technologies) of transcriptomes. The supervisory team comprises experts in C. elegans genetics and RNA biology, molecular biology and bioinformatics; the successful applicant will join a vibrant, international research team focussed on understanding a basic biology process with likely impacts on the global treatment of parasitic disease.

Application Procedure:

http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod at . Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to .

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership View Website. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.

References

Wenzel, M., Johnston, C., Müller, B., Pettitt, J., & Connolly, B. (2020). Resolution of polycistronic RNA by SL2 trans-splicing is a widely conserved nematode trait. RNA, rna-076414.

Pandarakalam GC, Speake M, McElroy S, Alturkistani A, Philippe L, Pettitt J, et al. A high-throughput screen for the identification of compounds that inhibit nematode gene expression by targeting spliced leader trans-splicing. Int J Parasitol Drugs Drug Resist. 2019;10: 28–37.

Philippe L, Pandarakalam GC, Fasimoye R, Harrison N, Connolly B, Pettitt J, et al. An in vivo genetic screen for genes involved in spliced leader trans-splicing indicates a crucial role for continuous de novo spliced leader RNP assembly. Nucleic Acids Res. 2017;45: 8474–8483.


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