Overview
In this project, you will utilise cutting-edge cell and molecular biology techniques to uncover how RNA splicing modulates the hypoxia response. You will generate important insights into gene expression systems controlling key biological processes, relevant to human physiology and disease, where oxygen-sensing and RNA splicing mechanisms play critical roles.
About this opportunity
Gene expression involves the conversion of genetic information into RNA, which is then translated into proteins. This process is a fundamental feature of all organisms and is necessarily highly regulated. RNA splicing is one key mechanism that generates RNA diversity, allowing a single gene to produce multiple RNA and protein products and greatly increasing the functional capacity of an organism’s genome. However, very little is known about how RNA splicing is controlled in response to cell stress, including changes in oxygen availability.
Oxygen is essential for life, providing the energy needed for cells to function. Oxygen levels fluctuate markedly in biological systems, and adaptation to oxygen fluctuations is crucial to the survival and function of multicellular eukaryotes. Reduced oxygen (hypoxia) triggers changes in gene expression for adaptation and survival, and is important in physiological processes, such as embryo development and wound healing, and diseases, such as cancer and neurodegeneration. Given the importance of oxygen-sensing and RNA splicing, uncovering how RNA splicing regulates oxygen adaptation is of major biological significance.
My recent research demonstrates that RNA splicing is monitored and controlled by oxygen, and I hypothesise that dynamic regulation of RNA splicing shapes responses to oxygen fluctuations. In this multidisciplinary project, you will (i) identify RNA splicing-driven changes to genes and proteins that occur in response to hypoxia, (ii) define the molecular mechanisms causing these changes, and (iii) determine the contribution of oxygen-regulated RNA splicing to critical adaptive responses to hypoxia.
To achieve these objectives, you will combine cutting-edge cell and molecular biology approaches, including transcriptomics, proteomics, and cell imaging in established human cancer and primary cell lines, which are highly amenable to genetic and biochemical manipulation, with well-characterised hypoxia response systems.
Furthermore, you will benefit from the outstanding infrastructure, facilities, and specialised hypoxia equipment available at the University of Liverpool, and join a collaborative team consisting of experts in RNA splicing (Prof Angus Lamond, University of Dundee), hypoxia (Prof Sonia Rocha), stress responses and RNA regulation (Dr Niall Kenneth, University of Liverpool), Drosophila biology to analyse oxygen-sensitive RNA splicing in vivo (Dr Marisa Merino, University of Liverpool), and proteomics (Prof Claire Eyers, University of Liverpool).
As part of the studentship, you will receive the full support of the structured PhD programme within the Department of Biochemistry, Cell and Systems Biology at the University of Liverpool. This includes assignment of a secondary supervisor, attendance and the opportunity to present your work at conferences and lab/department/institute seminars, and structured training and support across a range of topics throughout the programme.