Role of the polycomb protein EED in the propagation of repressive histone marks
ABSTRACT 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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ABSTRACT: Histone posttranslational modifications (PTMs) are important cellular signals that can be read by a large repertoire of PTM recognition modules (Jenuwein and Allis, 2001) to direct many DNA template-dependent activities. These PTM reader domains have been well documented for their ability to distinguish differently modified residues or unmodified residues (Kouzarides, 2007 and Yun et al., 2011). A recent study showed that the tandem bromo-PWWP domain of a tumor-suppressor protein ZMYND11 preferentially binds to histone H3.3 that is methylated at lysine 36, but not to methylated H3.1 (Wen et al., 2014), suggesting that the reader domain can even select for modified histone variants. The prevalent notion is that each chromatin regulator is equipped with a different combination of the PTM reading modules (Ruthenburg et al., 2007), which allows complexes that engage with nucleosomes in a multivalent fashion to achieve robust binding and high specificity (Yun et al., 2011). The nucleosomal surface targets for these readers can be on one histone; for instance, Trim24 utilizes a tandem plant homeobox domain (PHD)-Bromo domain to recognize H3K4me0 and H3K23Ac on the same histone tail (Tsai et al., 2010). The targets also can be within one nucleosome, such as in the case of the PRC2 complex, which binds to a nucleosome through multiple contacts, including H3K27me, the H3 tail and H4 tails (Margueron et al., 2009 and Murzina et al., 2008). Finally, nucleosomal targets can be spread over multiple nucleosomes, as has been shown for the SIR complex (Martino et al., 2009) and L3MBTL1 (Trojer et al., 2007). Another feature of chromatin structure that has emerged as a key recognition site for the chromatin complex is the linker DNA and the space between adjacent nucleosomes. Three examples reported so far are the following: the PRC2 histone methyltransferase complex prefers dense nucleosome arrays (Yuan et al., 2012); the Rpd3S histone deacetylase complex favors dinucleosome units that are spaced about 30–40 bp apart (Lee et al., 2013); and the SWR1 remodeler targets the longer linker and nucleosome-free regions (Ranjan et al., 2013). However, how combinations of these rather static interactions are coordinated to achieve synergetic binding remains largely unknown.Cell Reports 01/2015; 28(2). DOI:10.1016/j.celrep.2014.12.027 · 7.21 Impact Factor
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ABSTRACT: REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus.The EMBO Journal 09/2014; DOI:10.15252/embj.201488398 · 10.75 Impact Factor
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