Genome Regulation by Polycomb and Trithorax Proteins
2007; Cell Press; Volume: 128; Issue: 4 Linguagem: Inglês
10.1016/j.cell.2007.02.009
ISSN1097-4172
AutoresBernd Schuettengruber, Daniel Chourrout, Michel Vervoort, Benjamin Leblanc, Giacomo Cavalli,
Tópico(s)Legume Nitrogen Fixing Symbiosis
ResumoPolycomb group (PcG) and trithorax group (trxG) proteins are critical regulators of numerous developmental genes. To silence or activate gene expression, respectively, PcG and trxG proteins bind to specific regions of DNA and direct the posttranslational modification of histones. Recent work suggests that PcG proteins regulate the nuclear organization of their target genes and that PcG-mediated gene silencing involves noncoding RNAs and the RNAi machinery. Polycomb group (PcG) and trithorax group (trxG) proteins are critical regulators of numerous developmental genes. To silence or activate gene expression, respectively, PcG and trxG proteins bind to specific regions of DNA and direct the posttranslational modification of histones. Recent work suggests that PcG proteins regulate the nuclear organization of their target genes and that PcG-mediated gene silencing involves noncoding RNAs and the RNAi machinery. Epigenetic regulation of gene expression is necessary for the correct deployment of developmental programs and for the maintenance of cell fates. Polycomb group (PcG) and trithorax group (trxG) genes were discovered in Drosophila melanogaster as repressors and activators of Hox genes, a set of transcription factors that specify cell identity along the anteroposterior axis of segmented animals. Subsequent work has shown that PcG and trxG proteins form multimeric complexes that are not required to initiate the regulation of Hox genes, but rather to maintain their expression state after the initial transcriptional regulators disappear from the embryo. Subsequent work in Drosophila led to the identification of DNA regulatory elements that recruit PcG and trxG factors to chromatin in vivo. These elements, called PcG and trxG response elements (PREs and TREs), respectively, mediate epigenetic inheritance of silent and active chromatin states throughout development (reviewed in Muller and Kassis, 2006Muller J. Kassis J.A. Polycomb response elements and targeting of Polycomb group proteins in Drosophila.Curr. Opin. Genet. Dev. 2006; 16: 476-484Crossref PubMed Scopus (204) Google Scholar, Schwartz and Pirrotta, 2007Schwartz Y.B. Pirrotta V. Polycomb silencing mechanisms and the management of genomic programmes.Nat. Rev. Genet. 2007; 8: 9-22Crossref PubMed Scopus (693) Google Scholar). PcG and trxG genes have also been identified in vertebrates, where they also regulate Hox genes. In addition, PcG and trxG proteins are implicated in cell proliferation (reviewed in Martinez and Cavalli, 2006Martinez A.M. Cavalli G. The role of polycomb group proteins in cell cycle regulation during development.Cell Cycle. 2006; 5: 1189-1197Crossref PubMed Scopus (82) Google Scholar), stem cell identity and cancer (reviewed in Sparmann and van Lohuizen, 2006Sparmann A. van Lohuizen M. Polycomb silencers control cell fate, development and cancer.Nat. Rev. Cancer. 2006; 6: 846-856Crossref PubMed Scopus (1033) Google Scholar; also see review by Jones & Baylin, in this issue), genomic imprinting in plants and mammals (reviewed in Delaval and Feil, 2004Delaval K. Feil R. Epigenetic regulation of mammalian genomic imprinting.Curr. Opin. Genet. Dev. 2004; 14: 188-195Crossref PubMed Scopus (313) Google Scholar, Guitton and Berger, 2005Guitton A.E. Berger F. Control of reproduction by Polycomb Group complexes in animals and plants.Int. J. Dev. Biol. 2005; 49: 707-716Crossref PubMed Scopus (68) Google Scholar; Bernstein et al., in this issue) and X inactivation (reviewed in Heard, 2005Heard E. Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome.Curr. Opin. Genet. Dev. 2005; 15: 482-489Crossref PubMed Scopus (160) Google Scholar and Yang and Kuroda, this issue). An appreciation for the extensive biological roles for PcG and trxG proteins has motivated efforts to determine their mechanisms of action. Some trxG and PcG components possess methyltransferase activities directed toward specific lysines of histone H3, whereas other trxG and PcG proteins interpret these histone marks. Recent work has established the genome-wide distribution of PcG proteins, and considerable progress has been made toward understanding how PcG and trxG proteins are recruited to chromatin and how they regulate their target genes. Here, we discuss the molecular mechanisms of action of PcG and trxG proteins, their roles in regulating cell fate during development in eukaryotes, and analyze their functions from an evolutionary perspective. PcG proteins form three different classes of complexes (Table 1). Polycomb repressive complex 2 (PRC2) contains the four core components: E(z) (Enhancer of zeste), Esc (Extra sex combs), Su(z)12 (Suppressor of zeste 12) and Nurf-55 (in humans, EZH2, EED, SUZ12 and RbAp46/48). The SET domain-containing E(z) subunit trimethylates lysine 27 of histone H3 (H3K27me3) (reviewed in Cao and Zhang, 2004Cao R. Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3.Curr. Opin. Genet. Dev. 2004; 14: 155-164Crossref PubMed Scopus (694) Google Scholar). This mark is specifically recognized by the chromodomain of Polycomb (Pc) (Cao and Zhang, 2004Cao R. Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3.Curr. Opin. Genet. Dev. 2004; 14: 155-164Crossref PubMed Scopus (694) Google Scholar), a subunit of PRC1-type complexes. PRC1 contains Pc, Polyhomeotic (Ph), Posterior sex combs (Psc) and dRing, in addition to several other components, including TBP-associated factors (Saurin et al., 2001Saurin A.J. Shao Z. Erdjument-Bromage H. Tempst P. Kingston R.E. A Drosophila Polycomb group complex includes Zeste and dTAFII proteins.Nature. 2001; 412: 655-660Crossref PubMed Scopus (314) Google Scholar). Recently, a third complex involved in homeotic gene silencing, PhoRC, has been identified (Klymenko et al., 2006Klymenko T. Papp B. Fischle W. Kocher T. Schelder M. Fritsch C. Wild B. Wilm M. Muller J. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities.Genes Dev. 2006; 20: 1110-1122Crossref PubMed Scopus (292) Google Scholar). PhoRC includes the sequence specific DNA binding protein Pleiohomeotic (Pho) as well as the dSfmbt protein [Scm-related gene containing four malignant brain tumor (MBT) domains], which binds specifically to mono- and dimethylated H3K9 and H4K20 via its MBT repeats.Table 1PcG and trxG ComplexesDrosophila melanogasterHumanPcG complexesPhoRCdSfmbt?Pho?PRC2E(z)EZH2EscEEDSu(z)12SUZ12N55RpAp48RpAp46PRC1dRingRING1APcHPC1-3PhHPH1-3PscBMI1ScmSCMH1-2TBP-associated factorstrxG complexesSWI/SNFBrmBRMOsaBAF250MoiraBAF170Snr1BAF47NURFIswiSNF2LN38?N301BPTFN55RpAp46 RpAp48TAC1TrxaTrx is an ortholog of MLL proteins, but the TAC1 complex isolated in Drosophila is composed of proteins that differ from the subunits of the MLL complex. However, orthologs of the mammalian MLL core-complex subunits are present in the Drosophila genome, and therefore MLL-like complexes may exist in flies. Question mark indicates that the protein is present in human, but it is not known whether it forms the same complex as in flies.dCBPSbf1Ash1Ash1dCBPMLL1-3MLL1-3aTrx is an ortholog of MLL proteins, but the TAC1 complex isolated in Drosophila is composed of proteins that differ from the subunits of the MLL complex. However, orthologs of the mammalian MLL core-complex subunits are present in the Drosophila genome, and therefore MLL-like complexes may exist in flies. Question mark indicates that the protein is present in human, but it is not known whether it forms the same complex as in flies.WDR5ASH2LRbBP5CFP1Only the core components of each complex are shown.a Trx is an ortholog of MLL proteins, but the TAC1 complex isolated in Drosophila is composed of proteins that differ from the subunits of the MLL complex. However, orthologs of the mammalian MLL core-complex subunits are present in the Drosophila genome, and therefore MLL-like complexes may exist in flies. Question mark indicates that the protein is present in human, but it is not known whether it forms the same complex as in flies. Open table in a new tab Only the core components of each complex are shown. Neither PRC2 nor PRC1 core complexes contain sequence specific DNA binding proteins, but Pho has been shown to bind to PRC2 subunits and to induce PRC2 recruitment at the bxd PRE of the Ubx gene in Drosophila (Wang et al., 2004bWang L. Brown J.L. Cao R. Zhang Y. Kassis J.A. Jones R.S. Hierarchical recruitment of polycomb group silencing complexes.Mol. Cell. 2004; 14: 637-646Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar). A simple pathway for PcG protein recruitment has been suggested based on the stepwise recruitment of PRC2 proteins by Pho (and Pho-like, a protein that binds to the same DNA motifs), followed by PRC1 recruitment to the H3K27me3 mark deposited by PRC2. However, PcG recruitment is much more complex than this. Firstly, Pho is not only able to recruit PRC2, but it also interacts directly with the Pc and Ph subunits of PRC1 in vitro (Mohd-Sarip et al., 2002Mohd-Sarip A. Venturini F. Chalkley G.E. Verrijzer C.P. Pleiohomeotic can link polycomb to DNA and mediate transcriptional repression.Mol. Cell. Biol. 2002; 22: 7473-7483Crossref PubMed Scopus (108) Google Scholar). The presence of Pho enables the core complex of PRC1 (PCC) to bind specifically, and without the need of PRC2, to a short sequence motif that is present at natural PREs close to Pho sites (Mohd-Sarip et al., 2005Mohd-Sarip A. Cleard F. Mishra R.K. Karch F. Verrijzer C.P. Synergistic recognition of an epigenetic DNA element by Pleiohomeotic and a Polycomb core complex.Genes Dev. 2005; 19: 1755-1760Crossref PubMed Scopus (76) Google Scholar). Secondly, core PREs might be depleted of nucleosomes. Mohd-Sarip and colleagues studied the architecture of the ternary complex of PRE DNA, Pho and PCC that had been reconstituted in vitro. This complex wraps DNA around the protein component and, in the presence of 6 Pho binding sites and juxtaposed PC binding elements, it includes over 400 bp of DNA in this interaction. This argues against a nucleosomal structure for this PRE in vivo (Mohd-Sarip et al., 2006Mohd-Sarip A. van der Knaap J.A. Wyman C. Kanaar R. Schedl P. Verrijzer C.P. Architecture of a Polycomb Nucleoprotein Complex.Mol. Cell. 2006; 24: 91-100Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). The absence of core histones at the Ubx PRE is also supported by in vivo studies using chromatin immunoprecipitation (ChIP) (Kahn et al., 2006Kahn T.G. Schwartz Y.B. Dellino G.I. Pirrotta V. Polycomb complexes and the propagation of the methylation mark at the Drosophila Ubx gene.J. Biol. Chem. 2006; 281: 29064-29075Crossref PubMed Scopus (78) Google Scholar, Mohd-Sarip et al., 2006Mohd-Sarip A. van der Knaap J.A. Wyman C. Kanaar R. Schedl P. Verrijzer C.P. Architecture of a Polycomb Nucleoprotein Complex.Mol. Cell. 2006; 24: 91-100Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, Papp and Muller, 2006Papp B. Muller J. Histone trimethylation and the maintenance of transcriptional ONand OFF states by trxG and PcG proteins.Genes Dev. 2006; 20: 2041-2054Crossref PubMed Scopus (316) Google Scholar), which suggest that the H3K27me3 chromatin mark might not be the recruiter of PcG proteins at core PREs. Finally, Pho binding sites alone are insufficient to tether PcG proteins to DNA in vivo, even when multimerized or when the number of sites and the spacing between them is the same as in a natural PRE (Brown et al., 1998Brown J.L. Mucci D. Whiteley M. Dirksen M.L. Kassis J.A. The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1.Mol. Cell. 1998; 1: 1057-1064Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, Dejardin et al., 2005Dejardin J. Rappailles A. Cuvier O. Grimaud C. Decoville M. Locker D. Cavalli G. Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1.Nature. 2005; 434: 533-538Crossref PubMed Scopus (116) Google Scholar). Indeed, Pho can form a second complex with components of the INO80 nucleosome remodeling complex, and may play other roles in addition to recruitment of PcG proteins, which may be mediated by a subset of the genomic Pho binding sites (Klymenko et al., 2006Klymenko T. Papp B. Fischle W. Kocher T. Schelder M. Fritsch C. Wild B. Wilm M. Muller J. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities.Genes Dev. 2006; 20: 1110-1122Crossref PubMed Scopus (292) Google Scholar). Moreover, a Drosophila mutant lacking both Pho and Pho-like is lethal at a late developmental stage and, in mutant salivary glands, most PcG sites are stained normally in polytene chromosomes despite lack of detectable Pho protein (Brown et al., 2003Brown J.L. Fritsch C. Mueller J. Kassis J.A. The Drosophila pho-like gene encodes a YY1-related DNA binding protein that is redundant with pleiohomeotic in homeotic gene silencing.Development. 2003; 130: 285-294Crossref PubMed Scopus (140) Google Scholar), suggesting that other proteins can recruit PcG factors in the absence of Pho and Pho-like. GAGA factor (GAF), Pipsqueak, Dsp1, Grainyhead and members of the Sp1/KLF family have all been suggested to be involved in PcG recruitment (reviewed in Muller and Kassis, 2006Muller J. Kassis J.A. Polycomb response elements and targeting of Polycomb group proteins in Drosophila.Curr. Opin. Genet. Dev. 2006; 16: 476-484Crossref PubMed Scopus (204) Google Scholar). Mutations in these genes do not have a clear PcG phenotype and, intriguingly, all seem to be involved in activation as well as in silencing. One possibility is that a combination of several DNA binding factors, including as yet unknown components, could lead to tethering of PcG proteins to DNA in vivo. To date, PREs have only been characterized in Drosophila. In general, PREs can be simply defined as DNA elements necessary and sufficient for recruitment of PcG complexes and for PcG-dependent silencing of flanking promoters. Many of the PcG binding sites identified by chromatin immunoprecipitation in vertebrates might fit this criterion, and this prediction will be tested by transgenic assays. Their DNA sequences are likely to differ from fly PREs, because three of the DNA binding factors involved in PcG recruitment, GAF, Pipsqueak and Zeste, are not conserved in vertebrates. In addition to a “DNA code” and, possibly, the H3K27me3 mark, small RNAs and proteins of the RNAi machinery might be involved in PcG recruitment. It was shown that silencing mediated by a 3.6 kilobase DNA element from the Fab-7 regulatory region of the Abd-B Hox gene was relieved by mutations in the RNAi machinery (Grimaud et al., 2006Grimaud C. Bantignies F. Pal-Bhadra M. Ghana P. Bhadra U. Cavalli G. RNAi Components Are Required for Nuclear Clustering of Polycomb Group Response Elements.Cell. 2006; 124: 957-971Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Although the recruitment of PcG proteins was only slightly affected (suggesting that RNAi-independent mechanisms are sufficient to anchor PcG complexes at a majority of their endogenous target genes) a recent report shows that the human AGO1 homolog can drive transcriptional gene silencing of promoters targeted by specific small interfering RNAs (siRNAs) via recruitment of the PcG protein EZH2 (Kim et al., 2006Kim D.H. Villeneuve L.M. Morris K.V. Rossi J.J. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells.Nat. Struct. Mol. Biol. 2006; 13: 793-797Crossref PubMed Scopus (336) Google Scholar). However, the reported phenotypes caused by mutations in genes of the RNAi machinery are not similar to those seen in PcG mutants. Thus, RNAi components might act redundantly with DNA binding proteins at a subset of the PcG targets. Recruitment of trxG proteins is even more mysterious. TrxG proteins are a somewhat heterogeneous group (Table 1). One class of trxG members is composed of SET domain factors like Drosophila Trx and Ash1 and vertebrate MLL, as well as their associated proteins. A second class of trxG factors includes components of ATP-dependent chromatin remodeling complexes like the SWI/SNF or the NURF complexes. Vertebrate complexes containing homologs of Drosophila Trx and Ash1 proteins are recruited at Hox genes, but the mechanisms are unknown (Hughes et al., 2004Hughes C.M. Rozenblatt-Rosen O. Milne T.A. Copeland T.D. Levine S.S. Lee J.C. Hayes D.N. Shanmugam K.S. Bhattacharjee A. Biondi C.A. et al.Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.Mol. Cell. 2004; 13: 587-597Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, Wysocka et al., 2003Wysocka J. Myers M.P. Laherty C.D. Eisenman R.N. Herr W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3–K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1.Genes Dev. 2003; 17: 896-911Crossref PubMed Scopus (310) Google Scholar). In Drosophila, Trx binds a minimal Fab-7 element in salivary glands in the absence of transcriptional activation (Dejardin and Cavalli, 2004Dejardin J. Cavalli G. Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module.EMBO J. 2004; 23: 857-868Crossref PubMed Scopus (70) Google Scholar). Other work suggests that a second DNA element overlapping the bxd PRE upstream of Ubx is involved in Trx-dependent maintenance of Ubx activation (Tillib et al., 1999Tillib S. Petruk S. Sedkov Y. Kuzin A. Fujioka M. Goto T. Mazo A. Trithorax- and Polycomb-group response elements within an Ultrabithorax transcription maintenance unit consist of closely situated but separable sequences.Mol. Cell. Biol. 1999; 19: 5189-5202Crossref PubMed Google Scholar). Furthermore, Trx is reported to bind at this element irrespective of the state of Ubx expression in imaginal discs of Drosophila larvae (Papp and Muller, 2006Papp B. Muller J. Histone trimethylation and the maintenance of transcriptional ONand OFF states by trxG and PcG proteins.Genes Dev. 2006; 20: 2041-2054Crossref PubMed Scopus (316) Google Scholar), suggesting that specific DNA tethers recruit Trx independent of the action of transcription factors. In Drosophila embryos, Trx is observed to constitutively bind to the promoter regions of the Ubx gene and of the bxd element. Interestingly however, this paper also reports recruitment of Trx to transcribed Ubx regions, but only upon activation (Petruk et al., 2006Petruk S. Sedkov Y. Riley K.M. Hodgson J. Schweisguth F. Hirose S. Jaynes J.B. Brock H.W. Mazo A. Transcription of bxd Noncoding RNAs Promoted by Trithorax Represses Ubx in cis by Transcriptional Interference.Cell. 2006; 127: 1209-1221Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Thus, between the two papers there is a discrepancy in Trx location. However, the first study used antibodies directed against the C-terminal part of the protein, whereas in the latter study the antibody was directed against the N-terminal part. The Trx protein is proteolytically cleaved by the Taspase enzyme (Hsieh et al., 2003Hsieh J.J. Cheng E.H. Korsmeyer S.J. Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression.Cell. 2003; 115: 293-303Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), and the two moieties might target different chromatin regions upon cleavage. Other trxG components seem to be recruited to chromatin in an activation-dependent manner. For instance, upon Ubx activation Ash1 is recruited to the region immediately downstream the transcription start site (Papp and Muller, 2006Papp B. Muller J. Histone trimethylation and the maintenance of transcriptional ONand OFF states by trxG and PcG proteins.Genes Dev. 2006; 20: 2041-2054Crossref PubMed Scopus (316) Google Scholar). The SWI/SNF component Brm is also recruited to polytene chromosomes upon activation of a transgene carrying a minimal Fab-7 element (Dejardin and Cavalli, 2004Dejardin J. Cavalli G. Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module.EMBO J. 2004; 23: 857-868Crossref PubMed Scopus (70) Google Scholar). Interestingly, mutation of Zeste sites in the Fab-7 element prevents recruitment of Brm, but not of Trx. Thus, multiple DNA tethers cooperate for recruitment of trxG proteins needed for gene activation. In summary, recruitment of PcG and trxG proteins involves combinatorial signals from multiple DNA motifs. The simultaneous binding of multiple silencing and activating factors at PREs/TREs suggests that they build switchable regulatory platforms (Figure 1), which may be able to read early developmental cues and transform them into heritable states of gene expression or transcriptional silencing. PRC2-type complexes possess H3K27-specific trimethylase activity (Cao and Zhang, 2004Cao R. Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3.Curr. Opin. Genet. Dev. 2004; 14: 155-164Crossref PubMed Scopus (694) Google Scholar) whereas several trxG complexes have H3K4 trimethylase activity (Figure 2A). (Byrd and Shearn, 2003Byrd K.N. Shearn A. ASH1, a Drosophila trithorax group protein, is required for methylation of lysine 4 residues on histone H3.Proc. Natl. Acad. Sci. USA. 2003; 100: 11535-11540Crossref PubMed Scopus (112) Google Scholar, Dou et al., 2005Dou Y. Milne T.A. Tackett A.J. Smith E.R. Fukuda A. Wysocka J. Allis C.D. Chait B.T. Hess J.L. Roeder R.G. 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Yet, in the repressed state, the whole Ubx gene is trimethylated at H3K27. In contrast, in the active state, H3K27me3 is still present in the upstream region of the gene, but is virtually absent at the promoter and the coding region of the gene. The absence of H3K27 trimethylation in part of the gene correlates with the binding of Ash1 immediately downstream to the promoter, which induces trimethylation of H3K4. Trx binds constitutively at the PRE in the absence of detectable H3K4me3 around the PRE region (as revealed by an antibody directed against the C-terminal portion of the protein). The mammalian Trx homolog MLL1 is also responsible for H3K4 trimethylation at the human HOXA9 locus (Dou et al., 2005Dou Y. Milne T.A. Tackett A.J. Smith E.R. Fukuda A. Wysocka J. Allis C.D. Chait B.T. Hess J.L. Roeder R.G. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.Cell. 2005; 121: 873-885Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar), but a knockout of the SET domain of mouse Mll results in the specific depletion of monomethylated H3K4 (Terranova et al., 2006Terranova R. Agherbi H. Boned A. Meresse S. Djabali M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll.Proc. Natl. Acad. Sci. USA. 2006; 103: 6629-6634Crossref PubMed Scopus (149) Google Scholar) at the Hoxd4 and Hoxc8 genes. Thus, the role of Trx and MLL1 in histone methylation might be gene specific and might be assisted by additional histone methylase activities to produce the H3K4me3 mark associated with gene expression. Additional components might also be involved in H3K4 trimethylation. In yeast, H3K4 trimethylation requires monoubiquitylation of histone H2B at lysine 123 by Rad6/Bre1 (Sun and Allis, 2002Sun Z.W. Allis C.D. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.Nature. 2002; 418: 104-108Crossref PubMed Scopus (803) Google Scholar). Although Drosophila dBre1 has no known involvement in trxG-mediated activation, a complex between the proteins USP7 and GMP synthetase (GMPS) has been shown to contribute to PcG-mediated gene silencing via deubiquitylation of histone H2B (van der Knaap et al., 2005van der Knaap J.A. Kumar B.R. Moshkin Y.M. Langenberg K. Krijgsveld J. Heck A.J. Karch F. Verrijzer C.P. GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.Mol. Cell. 2005; 17: 695-707Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). This suggests a transhistone interplay between activating H3K4 trimethylation, stimulated by ubiquitylation of H2B, and silencing H3K27 trimethylation, stimulated by deubiquitylation of H2B (Figure 2B). In addition to H3K27 trimethylation, PRC2 containing a specific isoform of the EED protein is thought to catalyze trimethylation of lysine 26 of histone H1 (H1K26me3) (Kuzmichev et al., 2004Kuzmichev A. Jenuwein T. Tempst P. Reinberg D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3.Mol. Cell. 2004; 14: 183-193Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar). Surprisingly, similar experiments performed with recombinant complexes and di- or oligonucleosomes could not confirm whether it has the ability to methylate histone H1 (Martin et al., 2006Martin C. Cao R. Zhang Y. Substrate preferences of the EZH2 histone methyltransferase complex.J. Biol. Chem. 2006; 281: 8365-8370Crossref PubMed Scopus (76) Google Scholar), suggesting that differences in assay conditions can affect the histone substrate specificity of PRC2-type complexes. PcG complexes of the PRC1-type also contain an evolutionarily conserved histone modification activity leading to ubiquitylation of lysine 119 of histone H2A (H2AK119ub1, see Figure 2B) (de Napoles et al., 2004de Napoles M. Mermoud J.E. Wakao R. Tang Y.A. Endoh M. Appanah R. Nesterova T.B. Silva J. Otte A.P. Vidal M. et al.Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation.Dev. Cell. 2004; 7: 663-676Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar, Wang et al., 2004aWang H. Wang L. Erdjument-Bromage H. Vidal M. Tempst P. Jones R.S. Zhang Y. Role of histone H2A ubiquitination in Polycomb silencing.Nature. 2004; 431: 873-878Crossref PubMed Scopus (1197) Google Scholar), which is required for PcG-mediated silencing of the Drosophila Ubx gene (Wang et al., 2004aWang H. Wang L. Erdjument-Bromage H. Vidal M. Tempst P. Jones R.S. Zhang Y. Role of histone H2A ubiquitination in Polycomb silencing.Nature. 2004; 431: 873-878Crossref PubMed Scopus (1197) Google Scholar) as well as of the mouse HoxC13 gene (Cao et al., 2005Cao R. Tsukada Y.I. Zhang Y. Role of Bmi-1 and Ring1A in H2A Ubiquitylation and Hox Gene Silencing.Mol. Cell. 2005; 20: 845-854Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). A putative “reader” of this histone mark remains to be identified. Other histone modifications are associated with PcG and trxG proteins, although their role is not well understood. For instance, Papp and colleagues reported that trimethyhlation of H3K9 and H4K20 accompanies the H3K27me3 mark (Papp and Muller, 2006Papp B. Muller J. Histone trimethylation and th
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