Key Points
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Polycomb group (PcG) proteins were initially identified as crucial epigenetic regulators of homeotic genes in Drosophila species, but have recently been found to control hundreds of genes in insects and in mammals. The majority of PcG targets are key regulators of essentially all developmental pathways.
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PcG silencing involves at least three kinds of multiprotein complexes: PRC1, PRC2 and the newly discovered PhoRC. The RING component of PRC1 functions as a histone H2A lysine 119 ubiquitin ligase, whereas the PRC2 component Enhancer of zeste (E(Z)) has histone methyltransferase activity, which is directed towards lysine 27 of histone H3.
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In Drosophila, PcG silencing is directed to its target genes by specific DNA elements called Polycomb response elements (PREs). These elements are modular in nature and consist of clusters of sites for DNA-binding proteins, many of which remain to be discovered. Dense binding of proteins to the PRE DNA is incompatible with its organization in nucleosomes. Mammalian PREs have not been identified.
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PREs serve as binding platforms for PcG proteins, which can then work at considerable distances through DNA looping. We propose that such looping is principally responsible for the broad domain of histone H3 trimethylated at lysine 27 that is produced by PRC2 over the silenced gene. Histone methylation might, in turn, stabilize the PRE-bound complexes, but might also provide means for the long-distance interaction between the PRE and promoter.
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Recent experiments indicate that PcG silencing mechanisms do not involve higher order chromatin packaging, but rather direct the interaction between PcG proteins and transcriptional machinery. The mechanism of transcriptional interference is unknown, but could take many forms, including covalent modification of promoter or elongation factors; for example, by methylation or ubiquitylation mediated by PRC2 or PRC1.
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The spectrum of PcG targets indicates that PcG silencing functions as a general enforcement mechanism that is necessary for the maintenance of a genomic programme of gene expression. This in turn implies the existence of mechanisms to redirect PcG silencing should the state of differentiation be reprogrammed during development or tissue regeneration.
Abstract
Polycomb group complexes, which are known to regulate homeotic genes, have now been found to control hundreds of other genes in mammals and insects. First believed to progressively assemble and package chromatin, they are now thought to be localized, but induce a methylation mark on histone H3 over a broad chromatin domain. Recent progress has changed our view of how these complexes are recruited, and how they affect chromatin and repress gene activity. Polycomb complexes function as global enforcers of epigenetically repressed states, balanced by an antagonistic state that is mediated by Trithorax. These epigenetic states must be reprogrammed when cells become committed to differentiation.
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References
Lewis, E. B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).
Jurgens, G. A group of genes controlling the spatial expression of the bithorax complex in Drosophila. Nature 316, 153–155 (1985).
Poux, S., Horard, B., Sigrist, C. J. & Pirrotta, V. The Drosophila Trithorax protein is a coactivator required to prevent re-establishment of Polycomb silencing. Development 129, 2483–2493 (2002).
Klymenko, T. & Muller, J. The histone methyltransferases Trithorax and Ash1 prevent transcriptional silencing by Polycomb group proteins. EMBO Rep. 5, 373–377 (2004). References 3 and 4 provide evidence that the main role of TRX in the regulation of Hox genes is to prevent PcG silencing, rather than simply to activate their transcription.
Buchenau, P., Hodgson, J., Strutt, H. & Arndt-Jovin, D. J. The distribution of polycomb-group proteins during cell division and development in Drosophila embryos: impact on models for silencing. J. Cell Biol. 141, 469–481 (1998).
Gemkow, M. J., Verveer, P. J., Arndt-Jovin, D. J. Homologous association of the Bithorax-complex during embryogenesis: consequences for transvection in Drosophila melanogaster. Development 125, 4541–4552 (1998).
Sigrist, C. J. & Pirrotta, V. Chromatin insulator elements block the silencing of a target gene by the Drosophila Polycomb response element (PRE) but allow trans interactions between PREs on different chromosomes. Genetics 147, 209–221 (1997).
Bantignies, F., Grimaud, C., Lavrov, S., Gabut, M. & Cavalli, G. Inheritance of Polycomb-dependent chromosomal interactions in Drosophila. Genes Dev. 17, 2406–2420 (2003).
Vazquez, J., Müller, M., Pirrotta, V. & Sedat, J. W. The Mcp element mediates stable long-range chromosome–chromosome interactions in Drosophila. Mol. Biol. Cell 17, 2158–2165 (2006).
Heard, E. & Disteche, C. M. Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev. 20, 1848–1867 (2006).
Delaval, K. & Feil, R. Epigenetic regulation of mammalian genomic imprinting. Curr. Opin. Genet. Dev. 14, 188–195 (2004).
Grimaud, C. et al. RNAi components are required for nuclear clustering of Polycomb Group Response Elements. Cell 124, 957–971 (2006).
Shao, Z. et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 98, 37–46 (1999).
Saurin, A. J., Shao, Z., Erdjument-Bromage, H., Tempst, P. & Kingston, R. E. A Drosophila Polycomb group complex includes Zeste and dTAFII proteins. Nature 412, 655–660 (2001). These authors characterized the D. melanogaster PRC1 complex, indicating that TAFs might be components.
Dura, J. et al. A complex genetic locus, polyhomoeotic, is required for segmental specification and epidermal development in D. melanogaster. Cell 51, 829–839 (1987).
Wu, C.-T. & Howe, M. A genetic analysis of the Suppressor 2 of zeste complex of Drosophila melanogaster. Genetics 140, 139–181 (1995).
Beuchle, D., Struhl, G. & Müller, J. Polycomb group proteins and heritable silencing of Drosophila Hox genes. Development 128, 993–1004 (2001).
Brown, 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 130, 285–294 (2003).
Wang, L. et al. Alternative ESC and ESC-like subunits of a Polycomb group histone methyltransferase complex are differentially deployed during Drosophila development. Mol. Cell. Biol. 26, 2637–2647 (2006).
Levine, S. S. et al. The core of the Polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol. Cell. Biol. 22, 6070–6078 (2002).
Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003). This study provides a direct measurement of the affinity of the PC chromodomain to the amino terminus of histone H3 trimethylated at K27 and shows the crystal structure of the complex between the two, which explains the specificity of the interaction.
Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).
de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).
Cao, R., Tsukada, Y. & Zhang, Y. Role of BMi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005).
Buchwald, G. et al. Structure and E3-ligase activity of the Ring–Ring complex of Polycomb proteins Bmi1 and Ring1b. EMBO J. 25, 2465–2474 (2006).
Li, Z., Cao, R., Myers, M. P., Zhang, Y. & Xu, R.-M. structure of a Bmi-1-Ring1B Polycomb group ubiquitin ligase complex. J. Biol. Chem. 281, 20643–20649 (2006).
Czermin, B. et al. Drosophila Enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185–196 (2002).
Muller, J. et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197–208 (2002).
Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-Group silencing. Science 298, 1039–1043 (2002).
Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 16, 2893–2905 (2002). References 27–30 provide the first experimental proof of the histone methyltransferase activity of the PRC2 complex.
Polo, S. E. & Almouzni, G. Chromatin assembly: a basic recipe with various flavours. Curr. Opin. Genet. Dev. 16, 104–111 (2006).
Taylor-Harding, B., Binne, U. K., Korenjak, M., Brehm, A. & Dyson, N. J. p55, the Drosophila ortholog of RbAp46/RbAp48, is required for the repression of dE2F2/RBF-regulated genes. Mol. Cell. Biol. 24, 9124–9136 (2004).
Ketel, C. S. et al. Subunit contributions to histone methyltransferase activities of fly and worm Polycomb group complexes. Mol. Cell. Biol. 25, 6857–6868 (2005).
Schwartz, Y. B. et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nature Genet. 38, 700–705 (2006). High-resolution genome-wide mapping of PcG proteins and the trimethylated H3K27chromatin mark indicates that all of the main morphogenetic pathways in D. melanogaster are controlled by the PcG system. It also shows that PcG silencing is characterized by formation of broad trimethylated K27 domains and localized binding of PcG to PREs.
Ebert, A. et al. Su(var) genes regulate the balance between euchromatin and heterochromatin in Drosophila. Genes Dev. 18, 2973–2983 (2004). This article shows that, in D. melanogaster , all H3K27 methylation is E(Z) dependent and points out that half of D. melanogaster histone H3 is dimethylated at K27.
Ringrose, L., Ehret, H. & Paro, R. Distinct contributions of histone H3 lysine 9 and 27 methylation to locus-specific stability of polycomb complexes. Mol. Cell 16, 641–653 (2004).
Papp, B. & Muller, J. Histone trimethylation and the maintenance of transcriptional ON and OFF states by TrxG and PcG proteins. Genes Dev. 20, 2041–2054 (2006). Together with reference 67, this paper shows that trimethylated H3K27 marks the chromatin of the entire silenced Ubx gene, and the histone-poor PREs represent the principal binding sites for PcG proteins. These results argue against a role of methylation in the recruitment of PcG complexes to PREs.
Ng, J., Hart, C. M., Morgan, K. & Simon, J. A. A Drosophila ESC–E(Z) protein complex is distinct from other Polycomb group complexes and contains covalently modified ESC. Mol. Cell. Biol. 20, 3069–3078 (2000).
Tie, F., Prasad-Sinha, J., Birve, A., Rasmuson-Lestander, A. & Harte, P. J. A 1-megadalton ESC/E(Z) complex from Drosophila that contains Polycomblike and RPD3. Mol. Cell. Biol. 23, 3352–3362 (2003). This article indicates the existence of a larger species of the PRC2 complex, which contains PCL protein. It is possible that this PRC2 variant is responsible for K27 trimethylation at PcG target sites.
Furuyama, T., Banerjee, R., Breen, T. R. & Harte, P. J. SIR2 is required for Polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr. Biol. 14, 1812–1821 (2004).
Kuzmichev, A., Jenuwein, T., Tempst, P. & Reinberg, D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol. Cell 14, 183–193 (2004).
Kuzmichev, A. et al. Composition and histone substrates of Polycomb repressive group complexes change during cellular differentiation. Proc. Natl Acad. Sci. USA 102, 1859–1864 (2005).
Pasini, D., Bracken, A. P., Jensen, M. R., Denchi, E. L. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).
Montgomery, N. D. et al. The murine Polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr. Biol. 15, 942–947 (2005).
Brown, 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 1, 1057–1064 (1998).
Fritsch, C., Brown, J. L., Kassis, J. A. & Muller, J. The DNA-binding Polycomb group protein pleiohomeotic mediates silencing of a Drosophila homeotic gene. Development 126, 3905–3913 (1999).
Brown, 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 130, 285–294 (2003).
Satijn, D. P., Hamer, K. M., den Blaauwen, J. & Otte, A. P. The Polycomb group protein EED interacts with YY1, and both proteins induce neural tissue in Xenopus embryos. Mol. Cell. Biol. 21, 1360–1369 (2001).
Poux, S., Melfi, R. & Pirrotta, V. Establishment of Polycomb silencing requires a transient interaction between PC and ESC. Genes Dev. 15, 2509–2514 (2001).
Wang, L. et al. Hierarchical recruitment of Polycomb group silencing complexes. Mol. Cell 14, 637–646 (2004).
Klymenko, T. et al. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. Genes Dev. 20, 1110–1122 (2006). This paper describes the PhoRC complex, which contains the specific DNA-binding PHO protein.
Horard, B., Tatout, C., Poux, S. & Pirrotta, V. Structure of a Polycomb response element and in vitro binding of Polycomb group complexes containing GAGA factor. Mol. Cell. Biol. 20, 3187–3197 (2000).
Hodgson, J. W., Argiropoulos, B. & Brock, H. W. Site-specific recognition of a 70-base-pair element containing d(GA)(n) repeats mediates bithoraxoid Polycomb group response element-dependent silencing. Mol. Cell. Biol. 21, 4528–4543 (2001).
Brown, J. L., Grau, D. J., DeVido, S. K. & Kassis, J. A. An Sp1/KLF binding site is important for the activity of a Polycomb group response element from the Drosophila engrailed gene. Nucleic Acids Res. 33, 5181–5189 (2005).
Dejardin, J. et al. Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature 434, 533–538 (2005).
Müller, J. & Kassis, J. A. Polycomb response elements and targeting of Polycomb group proteins in Drosophila. Curr. Opin. Genet. Dev. 16, 476–484 (2006).
Tsukiyama, T., Becker, P. B. & Wu, C. ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature 367, 525–532 (1994).
Shopland, L. S., Hirayoshi, K., Fernandes, M. & Lis, J. T. HSF access to heat shock elements in vivo depends critically on promoter architecture defined by GAGA factor, TFIID, and RNA polymerase II binding sites. Genes Dev. 9, 2756–2769 (1995).
Mohd-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. 19, 1755–1760 (2005).
Ringrose, L., Rehmsmeier, M., Dura, J. M. & Paro, R. Genome-wide prediction of Polycomb/Trithorax response elements in Drosophila melanogaster. Dev. Cell 5, 759–771 (2003).
Tolhuis, B. et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nature Genet. 38, 694–699 (2006).
Negre, N. et al. Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol. 4, e170 (2006).
Struhl, G. & Brower, D. Early role of the esc+ gene product in the determination of segments in Drosophila. Cell 31, 285–292 (1982).
Rastelli, L., Chan, C. S. & Pirrotta, V. Related chromosome binding sites for zeste, Suppressors of zeste and Polycomb group proteins in Drosophila and their dependence on Enhancer of zeste function. EMBO J. 12, 1513–1522 (1993).
Edmunds, J. W. & Mahadevan, L. C. Protein kinases seek close encounters with active genes. Science 313, 449–451 (2006).
Schwartz, Y. B., Kahn, T. G. & Pirrotta, V. Characteristic low density and shear sensitivity of cross-linked chromatin containing polycomb complexes. Mol. Cell. Biol. 25, 432–439 (2005).
Kahn, 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. 281, 29064–29075 (2006). Together with reference 37, this article demonstrates that the chromatin of the silent Ubx gene is characterized by a broad trimethylated H3K27 domain and narrow peaks of PcG protein binding localized to histone-poor PREs. Furthermore, this study provides evidence that trimethylation of H3K27 spreads from the PRE, and that this spreading can be blocked by a chromatin insulator.
Mohd-Sarip, A. et al. Architecture of a Polycomb nucleoprotein complex. Mol. Cell 24, 91–100 (2006).
Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).
Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).
Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).
Squazzo, S. L. et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 16, 890–900 (2006).
Paro, R. & Hogness, D. S. The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila. Proc. Natl Acad. Sci. USA 88, 263–267 (1991).
Paro, R. Imprinting a determined state into the chromatin of Drosophila. Trends Genet. 6, 416–421 (1990).
Locke, J., Kotarski, M. A. & Tartof, K. D. Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect. Genetics 120, 181–198 (1988).
Hecht, A., Strahl-Bolsinger, S. & Grunstein, M. Spreading of transcriptional repressor SIR3 from telomeric heterochromatin. Nature 383, 92–96 (1996).
Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).
Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).
Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).
Francis, N. J., Saurin, A. J., Shao, Z. & Kingston, R. E. Reconstitution of a functional core Polycomb repressive complex. Mol. Cell 8, 545–556 (2001).
King, I. F., Francis, N. J. & Kingston, R. E. Native and recombinant Polycomb group complexes establish a selective block to template accessibility to repress transcription in vitro. Mol. Cell. Biol. 22, 7919–7928 (2002).
Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a Polycomb group protein complex. Science 306, 1574–1577 (2004).
Moshkin, Y. M. et al. The bithorax complex of Drosophila melanogaster: Underreplication and morphology in polytene chromosomes. Proc. Natl Acad. Sci. USA 98, 570–574 (2001).
Zhimulev, I. F. et al. Influence of the SuUR gene on intercalary heterochromatin in Drosophila melanogaster polytene chromosomes. Chromosoma 111, 377–398 (2003).
Ficz, G., Heintzmann, R. & Arndt-Jovin, D. J. Polycomb group protein complexes exchange rapidly in living Drosophila. Development 132, 3963–3976 (2005). The FRAP (fluorescence recovery after photobleaching) experiments that are described in this paper indicate that the binding of PcG to chromatin is highly dynamic.
Schlossherr, J., Eggert, H., Paro, R., Cremer, S. & Jack, R. S. Gene inactivation in Drosophila mediated by the Polycomb gene product or by position-effect variegation does not involve major changes in the accessibility of the chromatin fibre. Mol. Gen. Genet. 243, 453–462 (1994).
McCall, K. & Bender, W. Probes of chromatin accessibility in the Drosophila bithorax complex respond differently to Polycomb-mediated repression. EMBO J. 15, 569–580 (1996).
Boivin, A. & Dura, J. M. In vivo chromatin accessibility correlates with gene silencing in Drosophila. Genetics 150, 1539–1549 (1998).
Fitzgerald, D. P. & Bender, W. Polycomb group repression reduces DNA accessibility. Mol. Cell. Biol. 21, 6585–6597 (2001).
Dellino, G. I. et al. Polycomb silencing blocks transcription initiation. Mol. Cell 13, 887–893 (2004). This paper shows that, at least in some cases, PcG silencing does not restrict the access of transcription activators or RNA POL II complex, but directly affects the function of transcription machinery that are bound at the promoter.
Mallin, D. R., Myung, J. S., Patton, J. S. & Geyer, P. K. Polycomb group repression is blocked by the Drosophila suppressor of Hairy-wing [su(Hw)] insulator. Genetics 148, 331–339 (1998).
Comet, I. et al. PRE-mediated bypass of two Su(Hw) insulators targets PcG proteins to a downstream promoter. Dev. Cell 11, 117–124 (2006).
Muravyova, E. et al. Loss of insulator activity by paired Su(Hw) chromatin insulators. Science 291, 495–498 (2001).
Bloyer, S., Cavalli, G., Brock, H. W. & Dura, J. M. Identification and characterization of polyhomeotic PREs and TREs. Dev. Biol. 261, 426–442 (2003).
Chinwalla, V., Jane, E. P. & Harte, P. J. The Drosophila Trithorax protein binds to specific chromosomal sites and is co-localized with Polycomb at many sites. EMBO J. 14, 2056–2065 (1995).
Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. J. & Korsmeyer, S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995).
Smith, S. T. et al. Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex. Nature Cell Biol. 6, 162–167 (2004).
Roguev, A. et al. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone H3 lysine 4. EMBO J. 20, 7137–7148 (2001).
Miller, T. et al. COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc. Natl Acad. Sci. USA 98, 12902–12907 (2001).
Krogan, N. J. et al. The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation. Mol. Cell 11, 721–729 (2003).
Guenther, M. G. et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc. Natl Acad. Sci. USA 102, 8603–8608 (2005).
Steward, M. M. et al. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nature Struct. Mol. Biol. 13, 852–854 (2006).
Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature Struct. Mol. Biol. 13, 713–719 (2006).
Chen, X., Hiller, M., Sancak, Y. & Fuller, M. T. Tissue-specific TAFs counteract Polycomb to turn on terminal differentiation. Science 310, 869–872 (2005).
Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).
Lessard, J. & Sauvageau, G. Polycomb group genes as epigenetic regulators of normal and leukemic hemopoiesis. Exp. Hematol. 31, 567–585 (2003).
Park, I. K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).
Martinez, A. M., Colomb, S., Dejardin. J., Bantignies. F. & Cavalli, G. Polycomb group-dependent Cyclin A repression in Drosophila. Genes Dev. 20, 501–513 (2006).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006). This paper indicates that broad domains that are simultaneously enriched with trimethylated H3K27 and H3K4 mark PcG targets in mouse ES cells. This unusual chromatin state might be important for silencing of developmental genes in ES cells, while keeping them poised for activation.
O'Carroll, D. et al. The Polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).
Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006).
Hogga, I. & Karch, F. Transcription through the iab-7 cis-regulatory domain of the bithorax complex interferes with maintenance of Polycomb-mediated silencing. Development 129, 4915–4922 (2002).
Bender, W. & Fitzgerald, D. P. Transcription activates repressed domains in the Drosophila bithorax complex. Development 129, 4923–4930 (2002).
Rank, G., Prestel, M. & Paro, R. Transcription through intergenic chromosomal memory elements of the Drosophila bithorax complex correlates with an epigenetic switch. Mol. Cell. Biol. 22, 8026–8034 (2002).
Schmitt, S., Prestel, M. & Paro, R. Intergenic transcription through a Polycomb group response element counteracts silencing. Genes Dev. 19, 697–708 (2005). This work provides evidence that, at least under some circumstances, transcription through the PRE is necessary and sufficient for resetting its state into the positive maintenance element.
Dejardin, J. & Cavalli, G. Chromatin inheritance upon Zeste-mediated Brahma recruitment at a minimal cellular memory module. EMBO J. 23, 857–868 (2004).
Sanchez-Elsner, T., Gou, D., Kremmer, E. & Sauer, F. Noncoding RNAs of Trithorax response elements recruit Drosophila Ash1 to Ultrabithorax. Science 311, 1118–1123 (2006).
Cavalli, G. & Paro, R. The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis. Cell 93, 505–518 (1998).
Cavalli, G. & Paro, R. Epigenetic inheritance of active chromatin after removal of the main transactivator. Science 286, 955–958 (1999).
Hadorn, E. in The Genetics and Biology of Drosophila Vol. 2c (eds Ashburner, M. & Wright, T. R. F.) 556–617 (Academic, New York, 1978). This posthumous article summarizes a decade of work on transdetermination in the author's laboratory, and describes the basic rules for changes in identity of regenerating imaginal discs.
Maves, L. & Schubiger, G. A molecular basis for transdetermination in Drosophila imaginal discs: interactions between wingless and decapentaplegic signaling. Development 125, 115–124 (1998).
Klebes, A. et al. Regulation of cellular plasticity in Drosophila imaginal disc cells by the Polycomb group, trithorax group and lama genes. Development 132, 3753–3765 (2005).
Lee, N., Maurange, C., Ringrose, L. & Paro, R. Suppression of Polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs. Nature 438, 234–237 (2005). References 123–125 describe the analysis of events in the cells that change identity and explain that intense intercellular signalling suppresses PcG silencing and facilitates reprogramming of target genes.
Hobert, O., Jallal, B. & Ullrich, A. Interaction of Vav with ENX-1, a putative transcriptional regulator of homeobox gene expression. Mol. Cell. Biol. 16, 3066–3073 (1996).
Witte, V. et al. HIV-1 Nef mimics an integrin receptor signal that recruits the polycomb group protein Eed to the plasma membrane. Mol. Cell 13, 179–190 (2004).
Su, I. H. et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425–436. References 126–128 report the remarkable exodus of PRC2 from the nucleus to the cytoplasm in response to the activation of certain signalling pathways. In reference 126, the cytoplasmic PRC2 is shown to be necessary for the ensuing remodelling of the actin cytoskeleton.
Voncken, J. W. et al. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J. Cell Sci. 112, 4627–4639 (1999).
Voncken, J. W. et al. MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the Polycomb group protein Bmi1. J. Biol. Chem. 280, 5178–5187 (2005).
Cha, T.-L. et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of Lysine 27 in histone H3. Science 310, 306–310 (2005).
Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).
Goodrich, J. et al. A Polycomb-group gene regulates homeotic gene expression in Arabidopsis. Nature 386, 44–51 (1997).
Grossniklaus, U., Vielle-Calzada, J., Hoeppner, M. A. & Gagliano, W. B. Maternal control of embryogenesis by MEDEA, a Polycomb group gene in Arabidopsis. Science 280, 446–450 (1998).
Gendall, A. R., Levy, Y. Y., Wilson, A. & Dean, C. The VERNALIZATION 2 gene mediates the epigenetic regulation of vernalization in Arabidopsis. Cell 107, 525–535 (2001).
Guitton, A. E. & Berger, F. Control of reproduction by Polycomb group complexes in animals and plants. Int. J. Dev. Biol. 49, 707–716 (2005).
Hennig, L., Bouveret, R. & Gruissem, W. MSI1-like proteins: an escort service for chromatin assembly and remodeling complexes. Trends Cell Biol. 15, 295–302 (2005).
Makarevich, G. et al. Different Polycomb group complexes regulate common target genes in Arabidopsis. EMBO Rep. 7, 947–952 (2006).
Fong, Y., Bender, L., Wang, W. & Strome, S. Regulation of the different chromatin states of autosomes and X chromosomes in the germ line of C. elegans. Science 296, 2235–2238 (2002).
Kyba, M. & Brock H. W. The Drosophila Polycomb group protein Psc contacts Ph and Pc through specific conserved domains. Mol. Cell. Biol. 18, 2712–2720 (1998).
Levine, S. S., King, I. F. G. & Kingston, R. E. Division of labor in Polycomb group repression. Trends Biochem. Sci. 29, 478–485 (2004).
Cao, R. & Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14, 155–164 (2004).
Nekrasov, M., Wild, B. & Muller J. Nucleosome binding and histone methyltransferase activity of Drosophila PRC2. EMBO Rep. 6, 348–353 (2005).
Ketel, C. S. et al. Subunit contribution to the histone methyltransferase activities of fly and worm Polycomb group complexes. Mol. Cell. Biol. 25, 6857–6868 (2005).
Dellino, G. I., Tatout, C. & Pirrotta, V. Extensive conservation of sequences and chromatin structures in the bxd Polycomb response element among Drosophilid species. Int. J. Dev. Biol. 46, 133–141 (2002).
Richards, S. et al. Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution. Genome Res. 15, 1–18 (2005).
Ludwig, M. Z., Bergman, C., Patel, N. H. & Kreitman, M. Evidence for stabilizing selection in a eukaryotic enhancer element. Nature 403, 564–567 (2000).
Ludwig, M. Z. Functional evolution of noncoding DNA. Curr. Opin. Genet. Dev. 12, 634–639 (2002).
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Glossary
- Segmentation gene
-
One of a group of genes that specify the segmental pattern within the anterior–posterior body axis of Drosophila melanogaster and other arthropods.
- Gastrulation
-
A morphogenetic process in early embryogenesis, during which the endoderm, mesoderm and ectoderm germ layers are formed.
- Position-effect variegation
-
A phenomenon that was discovered in Drosophila melanogaster, which occurs when genes that are placed close to large heterochromatic regions are repressed. Typically, silencing occurs stochastically in some cells and their clonal descendants.
- Parasegment
-
Regions of the Drosophila melanogaster embryo that contain the posterior part of a hemisegment and the anterior part of its neighbour. They are patterned by segmentation genes. Mesodermal thickenings and ectodermal grooves demarcate parasegment borders.
- Haltere
-
A balancing organ that is located on the third thoracic segment in Diptera and is an evolutionary modification of a wing.
- Transvection
-
A phenomenon whereby homologous chromosomes are synapsed in somatic cells, and as a result some enhancers and/or silencers can function in trans.
- Polytene chromosomes
-
Chromosomes in many larval tissues that have replicated repeatedly without cell division and without separating the daughter DNA molecules, which remain aligned with one another.
- Vernalization
-
The mechanism that makes normal flowering dependent on the exposure of the plant to cold.
- Chromatin immunoprecipitation
-
A technique that isolates sequences from soluble DNA chromatin extracts (complexes of DNA and protein) by using antibodies that recognize specific chromosomal proteins.
- Tiling arrays
-
Microarrays containing evenly spaced genomic sequences representing the non-repetitive parts of the genome, often at high resolution.
- Scanning force microscopy
-
A microscopy technique that works by detecting the vertical position of a probe, which is in physical contact with the sample, while horizontally moving the probe relative to the sample.
- Chromatin insulators
-
Cis-acting DNA sequences that function as barriers to the effects of distal enhancers and silencers.
- Epigenetic state
-
Chromatin state that can be inherited by progeny cells and dictates the functional competence of a gene.
- Imaginal discs
-
An epithelial sheet that gives rise to external adult structures during insect metamorphosis, including the wings, eyes and antennae.
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Schwartz, Y., Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet 8, 9–22 (2007). https://doi.org/10.1038/nrg1981
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DOI: https://doi.org/10.1038/nrg1981
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