Tony Kouzarides PhD FRS FMedSci, Professor of Cancer Biology, Member of the Department of Pathology.
Epigenetic modifications and cancer
Do chromatin and RNA modifications offer therapeutic targets? DNA exists in the cell nucleus wrapped around histone proteins to form chromatin, a structure that must be navigated by the transcriptional machinery in order to ‘read’ the genetic code. The DNA and histones are decorated with many types of covalent chemical modifications, which can affect transcription and other cellular processes. In addition, non-coding RNAs that regulate chromatin function can be similarly chemically modified.
Our lab is involved in characterising the pathways that mediate DNA, RNA and histone modifications. We try to understand the cellular processes they regulate, their mechanism of action and their involvement in cancer.
We recently identified a novel modification of histones, methylation of glutamine, and showed that it regulates transcription; a different histone modification, citrullination, was shown to have a role in pluripotency; a novel RNA methyltransferase (BCDIN3D) was shown to be involved in cancer; and a small-molecule epigenetic inhibitor, I-BET, was shown to displace BET proteins from leukaemia genes and to be effective against MLL-leukaemia. I-BET is currently in clinical trials.
• Gilan O et al. (2016) Functional interdependence of BRD4 and DOT1L in MLL leukemia. Nat Struct Mol Biol. 2016 Jun 13. doi: 10.1038/nsmb.3249. [Epub ahead of print]
• Picaud S et al. (2015) Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy. Cancer Res. 75(23):5106-19.
• Viré E et al. (2014) The breast cancer oncogene EMSY represses transcription of antimetastatic microRNA miR-31. Mol Cell. 53(5):806-18.
• Christophorou MA et al. (2014) Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 507(7490): 104–108.
• Tessarz P et al. (2014) Glutamine methylation in histone H2A is an RNA- polymerase-I-dedicated modification. Nature 505(7484): 564–568.
• Dawson MA et al. (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 478(7370), 529-533