Role of non-coding RNA in ageing-dependent epigenetic changes in blood cancer

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Ageing is a major risk factor in cancer, and has a significant impact on disease progression and treatment outcomes in haematological cancers1. Although ageing has a genetic component, it appears that the majority of this risk is mediated by epigenetic mechanisms2. Cancer and ageing share some epigenetic hallmarks, including aberrant histone modifications and DNA methylation3. We predict that age-associated changes in epigenetic marks are caused by changes in the behaviour of the enzymes that catalyse these modifications.Previous work in the lab investigated CCDC26, a long non-coding RNA which is transcribed from a region rich in cancer-associated mutations4. This lncRNA was found to interact with and regulate DNMT1, the enzyme responsible for maintaining DNA methylation patterns in somatic cells. It is highly expressed in the chronic myeloid leukemia (CML) cell line, K562, where it is required for correct localisation of DNMT1 to the nucleus. CRISPR-Cas9 knockout of this lncRNA in K562 cells therefore leads to global DNA hypomethylation and DNA instability, causing reduced growth rates and increased apoptosis. This reveals a mechanism by which ncRNAs can modulate epigenetic changes, resulting in oncogenic effects.This project aims to expand on this research, investigating the role of ncRNAs such as CCDC26 in cancer-associated epigenetic changes, particularly those linked to ageing. The project supervisory team have expertise ranging from molecular and cellular biology to computational biology and genomics, and therefore can support a multidisciplinary approach to this research. Working with clinicians will maintain a translational focus, and allow for interpretation of results in a clinical context.1. Appelbaum, F. R. et al. Age and acute myeloid leukemia. Blood 107, 3481-3485 (2006).2. Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic Mechanisms of Longevity and Aging. Cell 166, 822-839 (2016).3. Aunan, J. R., Cho, W. C. & Soreide, K. The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis. 8, 628-642 (2017).4. Jones, R. et al. A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1. iScience 24, 102273 (2021).