One definitions 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.
1.
Thalhammer A, Hansen AS, El-Sagheer AH, Brown T, Schofield CJ: Hydroxylation of methylated CpG dinucleotides reverses stabilisation of DNA duplexes by cytosine 5-methylation [Internet]. Chem. Commun. 2011, Advance Article.
2.
Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C, Butler DS, Yates JR, et al.: Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing. Science 2009, 325: 90 -93.
3.
Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BMR, Bray JE, Savitsky P, Gileadi O, von Delft F, et al.: Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 2007, 448: 87-91.
4.
Gerken T, Girard CA, Tung Y-CL, Webby CJ, Saudek V, Hewitson KS, Yeo GSH, McDonough MA, Cunliffe S, McNeill LA, et al.: The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase. Science 2007, 318: 1469 -1472.
5.
Rose NR, Ng SS, Mecinović J, Liénard BMR, Bello SH, Sun Z, McDonough MA, Oppermann U, Schofield CJ: Inhibitor Scaffolds for 2-Oxoglutarate-Dependent Histone Lysine Demethylases⊥. Journal of Medicinal Chemistry 2008, 51: 7053-7056.
6.
Pollard PJ, Loenarz C, Mole DR, McDonough MA, Gleadle JM, Schofield CJ, Ratcliffe PJ: Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α. Biochem. J. 2008, 416: 387.
7.
Loenarz C, Schofield CJ: Oxygenase Catalyzed 5-Methylcytosine Hydroxylation. Chemistry & Biology 2009, 16: 580-583.
8.
Karkhanina AA, Mecinović J, Musheev MU, Krylova SM, Petrov AP, Hewitson KS, Flashman E, Schofield CJ, Krylov SN: Direct Analysis of Enzyme-Catalyzed DNA Demethylation. Analytical Chemistry 2009, 81: 5871-5875.
9.
Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CDO, Klose RJ, Ratcliffe PJ, Schofield CJ: PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nε-dimethyl lysine demethylase. Human Molecular Genetics 2010, 19: 217 -222.
10.
Sakurai M, Rose NR, Schultz L, Quinn AM, Jadhav A, Ng SS, Oppermann U, Schofield CJ, Simeonov A: A miniaturized screen for inhibitors of Jumonji histone demethylases. Mol. BioSyst. 2010, 6: 357-364.
11.
Hopkinson RJ, Hamed RB, Rose NR, Claridge TDW, Schofield CJ: Monitoring the Activity of 2-Oxoglutarate Dependent Histone Demethylases by NMR Spectroscopy: Direct Observation of Formaldehyde. ChemBioChem 2010, 11: 506-510.
12.
Mackeen MM, Kramer HB, Chang K-H, Coleman ML, Hopkinson RJ, Schofield CJ, Kessler BM: Small-Molecule-Based Inhibition of Histone Demethylation in Cells Assessed by Quantitative Mass Spectrometry. Journal of Proteome Research 2010, 9: 4082-4092.
13.
Kawamura A, Tumber A, Rose NR, King ONF, Daniel M, Oppermann U, Heightman TD, Schofield C: Development of homogeneous luminescence assays for histone demethylase catalysis and binding. Analytical Biochemistry 2010, 404: 86-93.
14.
Hopkinson RJ, Barlow PS, Schofield CJ, Claridge TDW: Studies on the reaction of glutathione and formaldehyde using NMR. Org. Biomol. Chem. 2010, 8: 4915-4920.
15.
Hahn P, Wegener I, Burrells A, Böse J, Wolf A, Erck C, Butler D, Schofield CJ, Böttger A, Lengeling A: Analysis of Jmjd6 cellular localization and testing for its involvement in histone demethylation. PloS one 2010, 5: e13769.
16.
King ONF, Li XS, Sakurai M, Kawamura A, Rose NR, Ng SS, Quinn AM, Rai G, Mott BT, Beswick P, et al.: Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase Inhibitors. PLoS ONE 2010, 5: e15535.
17.
Thalhammer A, Mecinovic J, Loenarz C, Tumber A, Rose NR, Heightman TD, Schofield CJ: Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates. Org. Biomol. Chem. 2011, 9: 127-135.