Tony Kouzarides - Overview

Many transcriptional regulators are found de-regulated in cancer. Our group is interested in defining the mechanisms by which such transcription factors function during normal cell proliferation and in cancer. Our attention is focused on a set of enzymes which modify histones and regulate transcription via chromatin remodelling. We would like to understand how, mechanistically, these modifications affect transcription, the biological role of histone modifying enzymes and their potential involvement in cancer.

Recently, we have focused on the process of histone methylation, which can occur on specific lysine or arginine residues. We have studied extensively methylation of lysine 9 of histone H3. This methylation leads to the transcriptional silencing of genes found in heterochromatin, and of cell cycle genes regulated by the Retinoblastoma (RB) repressor. Lysine 9 methylation mediates silencing by recruiting the repressor protein, HP1.

In contrast to methylation of lysine 9, methylation of lysine 4 on histone H3 is activatory for transcription. We have identified the enzymes in yeast that mediate methylation at lysine 4 and are now characterising their mammalian equivalents. We can show that lysine 4 methylation prevents the association of histones with Deacetylases, a process which would otherwise lead to repression.

A distinct set of enzymes methylate arginines. We have characterised one such methylase, CARM1, which is a regulation of nuclear hormone receptors. Our data show that CARM1 methylates arginine 17 of histone H3 in vivo and that this modification is deposited on histones when estrogen receptor-regulated genes are active.