BHF CRE Cardiovascular Medicinal Chemistry graduate student
Project: Probing the effect of hypoxia on epigenetic regulation by the histone demethylase KDM4A
Supervisors: Dr Akane Kawamura and Dr Emily Flashman.
The Cardiovascular Medicinal Chemistry DPhil programme appealed to me, because it truly sits at the interface of medical sciences and chemistry. At events such as the BHF CRE annual symposia and training seminars, we are able to get a real understanding of the cutting-edge cardiovascular research being done across the University, and an idea of how our chemical backgrounds can contribute to this. The CRE provides an excellent forum for sharing skills, techniques and expertise, and every event I have attended has provided an insight into how necessary and exciting a multi-disciplinary approach to research can be!
I started my DPhil in 2012, after completing a Chemistry (MChem) degree at the University of Oxford. The first 6 months of lectures and tutorials were a fantastic grounding in how the drug discovery process works, as well as an opportunity to learn differently and delve into the world of cardiovascular medicine. I developed an understanding of how disease states such as atherosclerosis, cardiac hypertrophy and heart failure arise and progress, and the challenges we face in treating these diseases, which are some of the leading causes of death worldwide. My first rotation was undertaken with Professor Angie Russell and Professor David Greaves, and involved the synthesis and testing of compounds that mediate macrophage chemotaxis for potential use in the treatment atherosclerosis. The recruitment of macrophages to lesions in blood vessel walls contributes to the formation of atherosclerotic plaques. If these plaques become inflamed and unstable, there is a risk of plaque rupture and a subsequent heart attack or strokes. Modulating the recruitment of macrophages is therefore a possible therapeutic strategy, and these compounds were being developed as tools to explore this further. This project highlighted how chemistry can impact upon our understanding and treatment of cardiovascular disease, and I learned a lot in a very short time!
My second rotation became my three-year DPhil project, and explored the potential involvement of the epigenetic modulator KDM4A in the development and progression of heart disease. A number of recent studies have shown that epigenetic marks (i.e. post-translational modifications on DNA and histone proteins that modulate gene expression) are dysregulated in cardiovascular disease states and in hypoxia and such dysregulation is likely to affect gene expression. My project focussed on the JmjC histone lysine demethylase (JmjC-KDM) KDM4A, which is responsible for removing methyl marks from lysine residues on the histone tails. The JmjC-KDMs are related to the cellular oxygen sensing HIF hydroxylase enzymes; hence the aim of my project was to investigate whether the activity of these enzymes may be sensitive to oxygen availability. Through in vitro and cellular studies, I found that lack of oxygen does have an impact upon KDM4A activity, which could have significant implications for epigenetic regulation in hypoxic disease states, including many cardiovascular diseases. We hope that future work will further explore the role of the JmjC-KDMs in the development and progression of these diseases, and assess the potential of these enzymes as therapeutic targets for small-molecule intervention.
Undergraduate degree: MChem, University of Oxford
Studentship dates: September 2012 intake. Thesis submitted January 2017.
Hancock RL, Masson N, Dunne K, Flashman E, Kawamura A. The Activity of JmjC Histone Lysine Demethylase KDM4A is Highly Sensitive to Oxygen Concentrations. ACS Chem Biol.
Hancock RL, Abboud MI, Smart TJ, Flashman E, Kawamura A, Schofield CJ, Hopkinson RJ. Lysine-241 Has a Role in Coupling 2OG Turnover with Substrate Oxidation During KDM4-Catalysed Histone Demethylation. Chembiochem. 2018 May 4;19(9):917-921. doi: 10.1002/cbic.201800002
Abboud MI, McAllister TE, Leung IKH, Chowdhury R, Jorgensen C, Domene C, Mecinović J, Lippl K, Hancock RL, Hopkinson RJ, Kawamura A, Claridge TDW, Schofield CJ. 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2.
Chem Commun (Camb). 2018 Mar 28;54(25):3130-3133. doi: 10.1039/c8cc00387d. Epub
Tarhonskaya H, Nowak RP, Johansson C, Szykowska A, Tumber A, Hancock RL, Lang P, Flashman E, Oppermann U, Schofield CJ, Kawamura A. Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates. J Mol Biol. 2017 Sep 15;429(19):2895-2906.