University of Dundee

MRC DTP 4 Year PhD Programme: Passive and active DNA demethylation pathways in stem cells and human diseases

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

The epigenetic mark of DNA methylation is established by DNMT (DNA methyltransferase) enzymes and has been shown to correlate with transcriptional states and influence cell identity and tumorigenesisin mammalian cells. The recent discovery that TET (Ten-Eleven-Translocation) enzymes produce 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxycytosine (5caC) andmediatepassive andactive DNA demethylation in the genome has opened a new avenue to understand how DNA methylation dynamics affect transcriptional programs(Rasmussen and Helin, 2016). Mutations in TET2 are frequently found (~10-50% of patients) in a wide range of blood diseases, including Acute Myeloid Leukemia (AML) and Myelodysplastic syndrome (MDS).However, the downstream events that cause hematopoietic stem cell to expand and transform following the occurrence of these mutations are currently unknown. While previous work has resulted in substantial advances, we still have an incomplete understanding of the pathways by which TET catalytic activity shape the DNA methylation landscape(Iwan et al, 2017). This PhD project will investigate questions relating to both passive and active DNA demethylation through the TET-mediated generation of 5hmC, 5fC and 5caCin the genome. We will employ new molecular and biochemical approaches to identify proteins with enzymatic activity towards the modified basesand investigate their relevance in stem cells and model systems of human diseases. At the completion of this project, the PhD candidate is expected to have obtained a strong skill set in biochemistry, epigenetics and proteomics.

Iwan, K., Rahimoff, R., Kirchner, A., et al. (2017). 5-Formylcytosine to cytosine conversion by C–C bond cleavage in vivo. Nature Chemical Biology, 14(1), 72–78.

Rasmussen, K. D., & Helin, K. (2016). Role of TET enzymes in DNA methylation, development, and cancer. Genes & Development, 30(7), 733–750.