Gamblin lab

Structural Biology of Disease Processes Laboratory

: Chromatin modification enzymes

We are interested in the molecular basis of the targeting and regulation of chromatin modification enzymes.

Epigenetic processes are an integral part of the mechanisms that define the gene expression program unique to different cell types. Chromatin modification enzymes are key components of epigenetic networks and are precisely targeted to nucleosomes associated with specific genes. The distinct patterns of marks placed by modification enzymes recruit effector proteins via their recognition domains.

The repressive Polycomb (PcG) and activating Trithorax (TRX) proteins regulate the expression of genes that determine cell fate. Both the PcG group protein EZH2, and TRX group MLL1, have histone lysine methylation activity, which is derived from their catalytic SET domains. In both enzymes the SET domain activity is dependent on the assembly of multi-protein complexes which are important for both targeting and allosteric regulation.

We are interested in how the interactions within these complexes target and regulate the activity of these enzymes and the potential for future therapeutic approaches.

One aspect of our work on epigenetic regulation is the functional and structural characterisation of the Polycomb Repressive Complex 2. We have previously shown (Margueron et al., 2009) that the aromatic cage of the EED component specifically binds histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2.

Our recent structure of the catalytic core of the human PRC2 (Justin et al., 2015) clarifies this mechanism and shows that the binding of the repressive mark is transmitted to the active site of the SET domain through the stabilisation of a series of helical elements. By stabilising the enzyme active site this promotes methyltransferase activity.