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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.
The fate of a cell is specified by its gene expression profile, often set early in development and maintained throughout the lifetime of the cell by epigenetic mechanisms. The polycomb group of proteins functions by silencing inappropriate expression by maintaining a repressive epigenetic state1. It is thought that the PRC2-mediated trimethylation of lysine 27 on histone H3 (H3K27me3) has a crucial role in marking repressive chromatin domains, whereas PRC1 is important for effecting transcriptional repression. Thus, once established, H3K27 trimethylation is the 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 twofold dilution caused by DNA replication in dividing cells. However, it is not yet clear how PRC2 complexes recognize previously marked sites and howthey accurately propagate these repressivemarks to unmodified nucleosomes deposited during DNA replication.
The histone lysine methyltransferase (HKMT) activity of the PRC2 complex resides in the SET-domain-containing protein EZH2 (refs 2-5), but activity requires the other subunits of the core complex; the zinc-finger-containing SUZ12 and the WD40 repeat proteins EED and RbAp48 (also known as CAF1). In certain contexts, the PHD-domain-containing protein PHF1 plays an important part in modulating the HKMT activity of PRC2 (refs 6, 7). In this work we have examined the structure and biochemistry of...