Confocal microscope image of embryonic mouse forepaw

Steve Gamblin group project:

Chromatin binding proteins

The Polycomb (PcG) group of proteins regulate the expression of fundamental genes that determine cell fate. PcG proteins are essential for stem cell maintenance and embryonic development. Three families of complexes containing PcG proteins have been identified in Drosophila to date: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2) and PhoRC.

The core of the PRC2 complex consists of four components: the catalytic subunit EZH2, EED, SUZ12 and RbAp46/48. PRC2 is the only known enzyme capable of di- and tri-methylating lysine 27 of histone H3, an event that is believed to be required to establish repression of PcG target genes. Intriguingly, although EZH2 harbours the methyltransferase activity within its SET domain, at least two other subunits (EED and SUZ12) are required for the functional activity of the complex.

Following up our previous work on the human histone methyltransferase SET7/9, we are currently undertaking functional and structural studies on the Polycomb Repressive Complex 2 (Figure 3). We have recently shown (Margueron, et al., 2009) that the aromatic cage of EED 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. Mutations in EED that prevent binding to repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and in Drosophila reduce global H3K27 methylation and interfere with development. Our work shows the functional and structural basis for epigenetic self-renewal and leads us to conclude that PRC2 readout of H3K27me3 is key to the propagation of this repressive mark.

Figure 3

Figure 3

Click image to view at full-size

Structures of chromatin binding proteins. Structure of SET7/9 with a histone H3 peptide and cofactor (a). Following this we determined the structure of EED in complex with a trimethylated H3K27 peptide (b).

Gamblin group

Recent publications

Research projects

Top of page

© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA