Margueron, R., Justin, N., Ohno, K., Sharpe, M. L., Son, J., Drury, W. J. 3rd et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461, 762-767
Howard Hughes Medical Institute and Department of Biochemistry, New York University Medical School, 522 First Avenue, New York, New York 10016, USA. Nature
(Impact Factor: 41.46).
09/2009; 461(7265):762-7. DOI: 10.1038/nature08398
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.
Available from: Sarah Geisler
- "The Esc subunit, on the other hand, acts as a scaffold to facilitate protein-protein interactions via its WD repeats (named for the tryptophan and aspartic acid residues that complete the repeat motif ) (O'Meara and Simon, 2012). Evidence from both Drosophila and mammalian systems suggests that Esc allosterically enhances PRC2 repression by imparting preferential binding to H3K27 trimethylation [the product of E(z) activity], thereby allowing local spreading of silencing (Margueron et al., 2009; O'Meara and Simon, 2012). The exact role of the p55 subunit appears to be more enigmatic. "
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ABSTRACT: Intricate layers of regulation determine the unique gene expression profiles of a given cell and, therefore, underlie the immense phenotypic diversity observed among cell types. Understanding the mechanisms that govern which genes are expressed and which genes are silenced is a fundamental focus in biology. The Polycomb and Trithorax group chromatin proteins play important roles promoting the stable and heritable repression and activation of gene expression, respectively. These proteins, which are conserved across metazoans, modulate post-translational modifications on histone tails and regulate nucleosomal structures. Here, we review recent advances that have shed light on the mechanisms by which these two classes of proteins act to maintain epigenetic memory and allow dynamic switches in gene expression during development.
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- "The recycling of modified parental histones offers an attractive epigenetic mechanism, as it ensures that histone marks are kept at their correct location on newly replicated DNA. Moreover, parental histones may also serve as a blueprint to modify neighboring new histones, given that modifications like H3K9 trimethylation (H3K9me3) and H3K27me3 can recruit their cognate enzyme and potentially be self-propagating (Aagaard et al. 1999; Hansen et al. 2008; Margueron et al. 2009). However, paradoxically , for several key modifications, mass spectrometry analysis showed that new histones had not acquired modifications to become identical to the old parental histones in the G1 phase of the next cell cycle (Scharf et al. 2009; Sweet et al. 2010; Xu et al. 2012). "
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ABSTRACT: Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.
Available from: Edith Heard
- "For example, the H3K4me3 and H3K36me3 marks associated to active transcription are reported to prevent the methylation of H3K27 by PRC2 when present on the same histone tail (Schmitges et al., 2011; Voigt et al., 2012; Yuan et al., 2011). In contrast, PRC2 enzymatic activity is stimulated by H3K27me3 via specific interactions between the methylated lysine 27 and the aromatic cage of Eed (Margueron et al., 2009) and by H2A ubiquitination (H2AUb) through a less defined molecular mechanism (Blackledge et al., 2014; Cooper et al., 2014; Kalb et al., 2014). Other chromatin features have also been shown to impact PRC2/chromatin interaction such as DNA methylation (Bartke et al., 2010) and nucleosome density (Simon and Kingston, 2013; Yuan et al., 2012). "
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ABSTRACT: Polycomb Group (PcG) proteins maintain transcriptional repression throughout development, mostly by regulating chromatin structure. Polycomb Repressive Complex 2 (PRC2), a component of the Polycomb machinery, is responsible for the methylation of histone H3 lysine 27 (H3K27me2/3). Jarid2 was previously identified as a cofactor of PRC2, regulating PRC2 targeting to chromatin and its enzymatic activity. Deletion of Jarid2 leads to impaired orchestration of gene expression during cell lineage commitment. Here, we reveal an unexpected crosstalk between Jarid2 and PRC2, with Jarid2 being methylated by PRC2. This modification is recognized by the Eed core component of PRC2 and triggers an allosteric activation of PRC2's enzymatic activity. We show that Jarid2 methylation is important to promote PRC2 activity at a locus devoid of H3K27me3 and for the correct deposition of this mark during cell differentiation. Our results uncover a regulation loop where Jarid2 methylation fine-tunes PRC2 activity depending on the chromatin context.
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