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Probing the effect of oxidative stress on epigenetic regulation

  • 1 November 2016 to 31 December 2017
  • Awards: Pump-priming Awards

Cardiovascular diseases such as cardiac hypertrophy and heart failure are characterised by distinct changes in gene expression. Recent studies have also found changes to the epigenetic landscape: the ‘code’ of modifications to DNA and associated histone proteins that regulates gene expression in response to environmental stimuli. Reactive oxygen species have been implicated in both cardiovascular disease states and changes to epigenetic modifications, including histone and DNA methylation. The overall aim of this project is to investigate the impact of ROS on the activity and function of the histone demethylase enzymes, which are responsible for modulating histone methylation, and related enzymes.  Subsequent effects on epigenetic regulation in a disease-specific context is necessary to provide valuable insight into the mechanism behind ROS-induced pathophysiology, and to aid in the discovery of viable biological targets for therapeutic intervention in cardiovascular disease. 

Publications linked to this award:

  1. Hancock, R. L., Masson, N., Dunne, K., Flashman, E., and Kawamura, A. (2017) The activity of JmjC histone lysine demethylase KDM4A is highly sensitive to oxygen concentrations. ACS Chem. Biol., 12 (4), pp 1011–1019 acschembio.6b00958.
  2. Wilkins, S. E., Abboud, M. I., Hancock, R. L., and Schofield, C. J. (2016) Targeting Protein-Protein Interactions in the HIF System. ChemMedChem 11, 773–86.
  3. Hancock, R. L., Dunne, K., Walport, L. J., Flashman, E., and Kawamura, A. (2015) Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7, 791–811.

  4. Hancock, R., Abboud, M., Smart, T., Flashman, E., Kawamura, A., Schofield, C. and Hopkinson, R. (2018). Lysine-241 Has a Role in Coupling 2OG Turnover with Substrate Oxidation During KDM4-Catalysed Histone Demethylation. ChemBioChem, 19(9), pp.917-921.