One definition of epigenetics is the transfer of genetic information between generations without a change in the 'ATCG' sequence of DNA. Methylation of cytosine bases in DNA is one established such mechanism, but the importance of other mechanisms, including histone modifications, is unclear. Recently, epigenetics has also been commonly used to refer to the mechanisms by which different patterns of gene expression are regulated, in particular at the transcriptional level. Stemming initially from our interest in the oxygen dependent regulation of expression in animals, we are interested in 'epigenetic' mechanism of regulation. A current focus is modification of histones, in particular oxygenase catalysed N-demethylation of histone methylated-lysine residues - in collaboration with the Structural Genomics Consortium. The histone demethylases are of interest both with respect to their links to diseases, including cancer and inflammatory diseases, as well as the role of methylation in transcriptional regulation. We are also interested in the identifying other oxygen dependent interfaces in the regulation of gene expression, particularly those that have pathophysiological relevance. Recent areas of interest include the fat mass and obesity protein which we have shown to be a nucleic acid demethylase and JMJD6 which is a lysyl hydroxylase modifying RNA splicing protein.
In collaboration with the Structural Genomics Consortium and industrial partners (including GlaxoSmithKline and Pfizer), we are developing small-molecule 'probes' for histone modifying and binding proteins. The current focus in our group is on enzymes from the JmjC family of histone demethylases.