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Role of the polycomb protein EED in the propagation of repressive histone marks


Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to 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 it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt 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.

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Figure 1: Trimethyl-lysine binding to an aromatic cage on EED.
Figure 2: Interactions between EED and trimethylated histone peptides.
Figure 3: EED and PRC2 interaction with chromatin.
Figure 4: Peptide mimicking repressive marks stimulates PRC2 activity.
Figure 5: The aromatic cage in Drosophila ESC is important for its in vivo function.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The structural data have been deposited with the Protein Data Bank under accession numbers 3IJC (EED/NDSB), 3IIW (EED/H3K27), 3IIY (EED/H1K26), 3IJ0 (EED/H3K9) and 3IJ1 (EED/H4K20).


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We thank D. McCabe for technical assistance, K. Basler for fly stocks and the pUASTattB plasmid, T. Jenuwein for antibodies and J. Muller for Drosophila PRC2 baculovirus. We thank J. Millar and A. Gould for suggestions and discussions, D. Allis for insightful discussions on histone specificity, P. Walker for technical assistance, and J. Brock for assistance with figures. This work was supported by the following grants: Fellowship from the Deutsche Akademie der Naturforscher Leopoldina (LPDS 2009-5) to P.V., NIH grants GM064844 and GM37120 and HHMI to D.R. Work in the S.J.G. laboratory is funded by the MRC. Work in the V.P. laboratory was supported by the Division of Life Sciences of Rutgers University.

Author Contributions R.M., N.J., K.O., M.L.S., J.S., W.J.D., P.V., S.R.M. and V.D.M. performed experiments. All authors contributed to data analysis, experimental design and manuscript writing.

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Correspondence to Vincenzo Pirrotta, Danny Reinberg or Steven J. Gamblin.

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Margueron, R., Justin, N., Ohno, K. et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762–767 (2009).

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