Tony Kouzarides PhD FMedSci, Royal Society Napier Professor, Member of the Pathology Department.
Function of chromatin modifications and their role in cancer
Our group is interested in defining the mechanisms by which chromatin modifications and non-coding (nc) RNAs regulate cellular processes. Our attention is focused on enzymes which regulate transcription by covalently modifying histones or ncRNAs. We would like to understand what biological processes these enzymes control and the precise role the modification has on chromatin dynamics. At the same time we are dissecting how modification pathways are mis-regulated in cancer cells and exploring avenues for treatment.
Our recent work has identified two new modification pathways that are implicated in cancer. The first pathway involves phosphorylation of tyrosine 41 of histone H3 by the JAK2, an enzyme found mutated in leukaemia. This modification functions by displacing the HP1 repressor protein from a key gene, LMO2, whose up-regulation is sufficient to cause leukaemia. The second pathway involves methylation of miRNA 145 by a new RNA enzyme BCDN3D. This modification disrupts the binding of miRNA 145 to dicer and therefore controls miRNA maturation. The BCDN3D enzyme is an oncogene with pro-metastatic characteristics, indicating that this pathway may be therapeutically important.
Recently we identified a histone acetylation pathway as being a good target for therapeutic intervention. The BET bromodomain proteins were shown to be involved in activating genes regulated by MLL-fusions, gene products responsible for MLL-leukaemias. A small molecule inhibitor of BETs (I-BET) was used to prevent the binding of BET proteins to acetylated histones and suppress this gene program. The I-BET molecule effectively inhibits primary human leukaemias and halts the process of leukaemia in model systems. Together these data give hope for the development of a therapeutic agent against MLL-leukaemias.
• Xhemalce B, Robson SC and Kouzarides T (2012) Human RNA methyltransferase BCDIN3D regulates microRNA processing. Cell, 12;151(2):278–88.
• Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Rober ts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ and Kouzarides T (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 478(7370), 529-533
• BartkeT,Vermeulen M,Xhemalce B,Robson SC,Mann M and Kouzarides T (2010). Nucleosome-interacting Proteins Regulated by DNA and Histone Methylation.Cell, 143: 470 – 84