Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains.

By W. Fischle, Yanming Wang, S. Jacobs, Youngchang Kim, C. D. Allis, S. Khorasanizadeh. Genes & Development, 2003

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On the histone H3 tail, Lys 9 and Lys 27 are both methylation sites associated with epigenetic repression, and reside within a highly related sequence motif ARKS. Here we show that the chromodomain proteins Polycomb (Pc) and HP1 (heterochromatin protein 1) are highly discriminatory for binding to these sites in vivo and in vitro. In Drosophila S2 cells, and on polytene chromosomes, methyl-Lys 27 and Pc are both excluded from areas that are enriched in methyl-Lys 9 and HP1. Swapping of the chromodomain regions of Pc and HP1 is sufficient for switching the nuclear localization patterns of these factors, indicating a role for their chromodomains in both target site binding and discrimination. To better understand the molecular basis for the selection of methyl-lysine binding sites, we solved the 1.8 A structure of the Pc chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared it with our previously determined structure of the HP1 chromodomain in complex with a H3 peptide bearing trimethyl-Lys 9. The Pc chromodomain distinguishes its methylation target on the H3 tail via an extended recognition groove that binds five additional residues preceding the ARKS motif.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bc9f345e86571b66cc6640253cb2f9df2cced709

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Citations in the corpus

Molecular Interplay of the Non-coding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a (2010, neutral): “The structure is similar to that of other chromodomains bound to H3 peptides including mouse HP1bCD/H3K9me2 and 668 Molecular Cell 38, 662–674, June 11, 2010 ª2010 Elsevier Inc. Drosophila PcCD/H3K27me3 (Fischle et al., 2003; Jacobs and Khorasanizadeh, 2002; Min et al., 2003; Nielsen et al., 2002).”
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Global Quantitative Modeling of Chromatin Factor Interactions (2014, background): “…(DCC) components MOF - MSL1 [20], PhoRC complex components Pho – dSFMBT [21], Polycomb-repressed chromatin mark and binding protein Pc - H3K27me3 [22], heterochromatin mark and binding protein H3K9me3 - HP1 [23], gypsy insulator complex components CP190 - mod(mdg4) [24], and heterochromatin mark…”
Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. (2010, background): “Such so-called phospho-methyl switches are quite common on core histones (Fischle et al., 2003a).”
Genome-wide analysis of Polycomb targets in Drosophila melanogaster (2006, background): “Mono- and dimethylated Lys27 is widely distributed in the genome, but PcG sites characteristically contain trimethylated Lys27 (me3K27”
Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, neutral): “Whereas the PRC2dependent mark H3K27me3 increases the affinity for Pc/CBXcontaining PRC1 complexes to chromatin (Fischle et al., 2003; Min et al., 2003), recent evidence in mammals suggests the existence of a recruiting step upstream of this canonical hierarchy (Figure 2A).”
Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. (2005, background): “HP1 isoforms interact with the H3 N terminus peptides containing di- and trimethylated H3-K9 with similar binding constants in vitro (Fischle et al. 2003).”
Mechanisms of Polycomb gene silencing: knowns and unknowns (2009, background): “The affinity of the chromodomain of Polycomb , a PRC1 constituent, for H3K27me3 (Ref”
Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. (2004, background): “Muller et al., 2002; Cao et al., 2002; Kuzmichev et al., 2002; Fischle et al., 2003; Min et al., 2003).”
Histone Tails and the H3 αN Helix Regulate Nucleosome Mobility and Stability (2007, background): “These include the chromodomains of HP1 and PRC1, which interact specifically with histones methylated at histone H3 lysine 9 and 27, respectively (4, 14, 27), and bromodomain-containing proteins which bind acetylated histone tails (26, 42).”