Polycomb proteins and repressive histone marks
NIMR scientists have described how repressive chromatin domains are maintained and transmitted. The article is published online in Nature.
A cell’s fate is specified by its gene expression profile, often set early in development and maintained throughout the life-time of the cell by epigenetic mechanisms. The Polycomb Group (PcG) proteins function by silencing inappropriate expression by maintaining a repressive epigenetic state. Polycomb Repressive Complex 2 (PRC2) mediates trimethylation of lysine 27 on histone H3 (H3K27) which acts as a key epigenetic mark for maintaining transcriptional repression. Mechanisms are therefore required to maintain this mark in repressed chromatin domains in non-dividing cells and to restore it after the two-fold dilution caused by DNA replication in dividing cells.
Steve Gamblin's laboratory, in NIMR's Division of Molecular Structure, collaborating with Danny Reinberg at NYU and Vince Pirrotta at Rutgers University, have examined the structure and biochemistry of Eed, a subunit of the PRC2 complex, and determined the role of its homologue in Drosophila development. From this they have established that the Eed subunit of PRC2 binds to repressive methyl-lysine marks ensuring the propagation of H3K27 trimethylation by activating the methyltransferase activity of the complex. Mutations in Eed that prevent it from recognising repressive trimethyl-lysine marks abolish activation of PRC2 in vitro and, in Drosophila, reduces global methylation and disrupts development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission of a histone modification from mother to daughter cells.
Trimethyl-lysine binding to an aromatic cage on EED
Ribbons representation of the EED-H3K27me3 complex, in which EED is in grey and the histone peptide is in yellow with its methyl-lysine side chain shown in stick representation.
This work was carried out in collaboration with Steve Martin in the Division of Physical Biochemistry and Willie Taylor in the Division of Mathematical Biology and with advice and guidance from Alex Gould in Developmental Neurobiology.
Steve Gamblin said:
"Chromatin domains are distinguished by the presence of a characteristic set of epigenetic marks. Eukaryotic cells must have the means of propagating these marks through cellular division and of ensuring that they obey appropriate boundaries during development. Our work shows the structural and functional basis for epigenetic self-renewal and leads us to conclude that PRC2 readout of H3K27me3, and to a lesser extent other repressive marks, is key to the propagation of this repressive mark."
Original article
The research findings are published in full in:
Raphael Margueron, Neil Justin, Katsuhito Ohno, Miriam L Sharpe, Jinsook Son, William J
Drury III, Philipp Voigt, Stephen Martin, William R. Taylor, Valeria De Marco, Vincenzo Pirrotta,
Danny Reinberg & Steven J. Gamblin (2009).
Role of the polycomb protein Eed in the propagation of repressive histone marks
Nature, epub ahead of print. Publisher abstract
Internal links
[22 September 2009]