As an intermediate molecule in the flow of genetic information, RNA offers a critical junction in the cell to regulate many cellular processes that underpin cell biology, development and tissue function. All classes of RNA can be chemically modified and it’s now emerging that the modification status of an RNA can affect its fate and function. The most common mRNA modification is known as m6A methylation and functions by recruiting the so-called effector m6A reader proteins to modified RNAs. Once bound these m6A reader proteins determine RNA processing events. Not surprisingly, viruses of medical importance manipulate the host cell RNA modification machinery to enhance virus replication.
The human tumour virus, Kaposi’s sarcoma-associated herpesvirus is the cause of the most common HIV-associated cancer in Africa, Kaposi’s sarcoma, and two other lymphoproliferative diseases. We have recently shown that KSHV-encoded RNAs are heavily m6A modified and that the modification of host cell RNAs is drastically altered during infection (Baquero et al., (2019) eLife, 8:e47261). This project now aims to determine how and why KSHV manipulates the host cell RNA modification machinery. Specifically, we aim to address the key question of why the m6A modification status of host cell RNAs are altered and how this enhances KSHV replication. This may provide new avenues to antiviral strategies for this important human pathogen of global importance.
As part of the Whitehouse group you will become part of an active research group which spans the interface between virology and RNA biology. This project is also part of an active collaboration with the Wilson group at Sheffield who have complementary experience in transcriptome analysis. This project can only be achieved using an interdisciplinary approach, using molecular virology and cell biology, coupled with NGS transcriptomic analysis and bioinformatics. As such, you will be provided training in (i) a wide range of live cell and confocal imaging approaches (ii) molecular cell biology techniques (iii) virological techniques (iv) bioinformatics approaches to analyse transcriptome and CLIP-seq data and (v) quantitative skills to analyse differential expression patterns.
More information about research in the Whitehouse laboratory can be found at : http://www.fbs.leeds.ac.uk/staff/Whitehouse_A/ @WhitehouseLab
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/
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: https://goo.gl/8YfJf8
Baquero-Pérez, B. et al (2019). The Tudor SND1 protein is an m6A RNA reader essential for KSHV replication. eLife, 8:e47261.
Manners, O. et al., (2019). Epitranscriptomics: widespread regulatory control in virus replication. BBA Gene Regulatory Mechanisms, BA - Gene Regulatory Mechanisms 1862, 370–381.
Manners, O. et al., (2018). Contribution of the KSHV and EBV Lytic Cycles to Tumourigenesis. Current Opinions in Virology, 32, 60–70.