Cancer-associated changes in gene expression and genome stability are often attributed to variations in DNA methylation. This is particularly true for blood cancers such as Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin’s Lymphomas (NHL) with increasing incidence/rates in the elderly. Ageing-associated changes in epigenetic modifications like DNA methylation result in increased burden of coexisting diseases and frailty, that impacts treatment choices, tolerance, and outcomes. DNA methylation is maintained by the enzyme DNA methyl-transferase-1 or DNMT1 whose activity is affected in age-dependent manner. Our recent findings (Jones et al, 2021, iScience) show that DNMT1 activity is regulated by non-protein-coding RNAs (ncRNAs). CRISPR-mediated removal of selected ncRNAs display genomic and cellular changes (such as DNA hypomethylation, signs of DNA instability, changes in cell cycle) similar to that observed in ageing cancer cells. To understand ageing-associated changes in DNA methylation and their association with cancer, there is a need study how DNMT1 methylation is regulated by its interaction with ncRNAs.
This project aims to understand the interplay of ncRNAs and DNA methylation in blood cancers such as CLL and NHL.
The supervisory team (Dr A Kanhere, Prof N Kalakonda and Dr G Strathdee has expertise in RNA biology, transcriptomics, epigenetics and computational biology. The recruited PhD student will use modern techniques such as transcriptomics and CRISPR-Cas9 mediated genome engineering alongside molecular and cell biology approaches to investigate the molecular mechanisms underlying ncRNA mediated regulation of DNA methylation. The study will utilise cancer cell line models and primary patient samples. This is a unique opportunity to work in a multi-disciplinary environment in two world-leading universities in the UK. In addition to scientific training, there is ample opportunity to acquire communication and presentation skills at scientific meetings and many opportunities for publications. Such experience should help establish a scientific career in academia or industry.
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, York 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 and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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