Our group is interested in defining the mechanisms by which chromatin modifications function to regulate cellular processes. Our attention is focussed on a set of enzymes (acetylases, deacetylases, methylases and kinases), which regulate transcription by covalently modifying histories. We would like to understand what biological processes these enzymes control and the precise role of each modification on chromatin dynamics. In addition we are dissecting as far as possible, how modification pathways are mis-regulated in cancer cells.

Histones are very highly modified.This complexity is necessary because histones integrate many signalling pathways regulating DNA function. We are taking a number of complementary approaches to characterise the role of chromatin modifications. We are using yeast as a model system whenever possible to define new pathways and we are using human cells to characterise their function in higher organisms and probe connections to cancer.

Modifications work by the recruitment of proteins. We have developed an assay for capturing proteins that recognise differentially modified nucleosomes, called SNAP (Silac Nucleosome Affinity Purification).This approach
has been successfully used to identify proteins that are sensitive to nucleosomes methylated on histones and DNA, thus defining categories of ‘cross talk’ between these two distinct classes of modification.

Recently we have shown that a set of bromodomain proteins called BET are involved in activating a set of genes regulated by MLL-fusions, the gene products responsible for MLL-leukaemias. A small molecule inhibitor of BETs, called I-BET which prevents them from binding to acetylated histones, is able to suppress this gene program in 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.

Chromatin-modifying enzymes are deregulated in cancer.

Selected publications:

• 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

• Xhemalce B and Kouzarides T (2010) A chromodomain switch mediated by histone H3 Lys 4 acetylation regulates heterochromatin assembly. Genes Dev 24(7), 647-652

• Dawson MA, Bannister AJ, Göttgens B, Foster SD, Bar tke T, Green AR and Kouzarides T (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461(7265), 819-822

• Santos-Rosa H, Kirmizis A, Nelson C, Bartke T, Saksouk N, Cote J and Kouzarides T (2009) Histone H3 tail clipping regulates gene expression. Nat Struct Mol Biol 16(1), 17-22

Model for the nuclear role of JAK2 in normal cells and in leukaemias containing JAK2 mutations.

The SNAP approach identifies 'cross-talk' between modifications in nucleosomes