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MRC DTP: Passive and active DNA demethylation pathways in stem cells and human diseases


School of Life Sciences

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Dr K Rasmussen , Dr Satpal Virdee No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the 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 tumorigenesis in mammalian cells. The recent discovery that TET (Ten-Eleven-Translocation) enzymes can oxidise methylated bases in the genome and produce 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), 5-carboxycytosine (5caC) and mediate passive and active DNA demethylation has opened a new avenue to understand how DNA methylation dynamics affect transcriptional programs and development of diseases (Rasmussen and Helin, Genes Dev 2016). Mutations in TET2 are frequently found in the aging population (a condition known as age-related “clonal hematopoiesis” that predispose individuals to atherosclerosis, venous thrombosis and heart failure (Steensma and Ebert, Exp Hemat. 2020)) as well as in a wide range of overt blood diseases. However, the events that cause hematopoietic stem cell to expand and transform following the occurrence of these mutations are currently unknown. Understanding the basic mechanisms that govern preleukaemic stem cells can therefore aid in the identification of ways to prevent disease and promote healthy aging.

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. This 4-year PhD project will investigate questions relating to both passive and active DNA demethylation through the TET-mediated generation of 5hmC, 5fC and 5caC in the genome. We will employ new molecular and biochemical approaches to identify proteins with enzymatic activity towards the modified bases and 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.

The research will be undertaken in the Rasmussen lab at the Centre for Gene Regulation & Expression (GRE) in the School of Life Sciences. The applicant will also work with the second supervisor Satpal Virdee in the MRC protein phosphorylation and ubiquitylation unit to design and use advanced biochemical methods to analyse aspect of DNA demethylation pathways. Training for all aspects of the project will be provided from the lab and through available skills-based courses at the University of Dundee.





References

Rasmussen, K. D. et al. TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. Genome Res. 29, 564–575 (2019).

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

Rasmussen, K. D. et al. Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Dev. 29, 910–922 (2015).


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