EASTBIO: Investigating the epigenetic basis of preleukaemic stem and progenitor cells to promote healthy aging

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 and DNMT3A 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.

This 4-year PhD Project will investigate the impact of mutations in TET2 and DNMT3A using physiological relevant model systems of normal hematopoiesis as well as mouse models of leukaemia previously established in the lab (Rasmussen et al, Genome Res 2019). The student will use the latest next-generation sequencing technologies to map alterations to the DNA methylation landscape and correlate this with transcriptional and phenotypic changes during hematopoietic differentiation. A further aim would be to establish CRISPR/Cas9 gene editing in these cells to manipulate the affected transcriptional programs and identify possible therapeutic interventions targeting mouse and human preleukaemic hematopoietic cells to promote healthy aging.

The research will be undertaken in the Centre for Gene Regulation & Expression (GRE) in the School of Life Sciences – a centre of excellence with >10 scientific groups working on various aspects of gene regulation and cellular biology. The applicant will also work closely with the second supervisor Gabriele Schweikert in the division of computational biology to use advanced computational methods to analyse the data. Training for all aspects of the project will be provided from the lab and through available skills-based courses at the University of Dundee. Applicants with an interest in epigenetics and gene regulation in blood diseases are most welcome to contact Kasper on [Email Address Removed] and/or visit the lab for an informal talk.