Artykuły w czasopismach: „Complexe polycomb”

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Dong, Guan-Jun, Jia-Le Xu, Yu-Ruo Qi, Zi-Qiao Yuan i Wen Zhao. "Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer". International Journal of Molecular Sciences 23, nr 17 (24.08.2022): 9574. http://dx.doi.org/10.3390/ijms23179574.

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Polycomp group (PcG) proteins are members of highly conserved multiprotein complexes, recognized as gene transcriptional repressors during development and shown to play a role in various physiological and pathological processes. PcG proteins consist of two Polycomb repressive complexes (PRCs) with different enzymatic activities: Polycomb repressive complexes 1 (PRC1), a ubiquitin ligase, and Polycomb repressive complexes 2 (PRC2), a histone methyltransferase. Traditionally, PRCs have been described to be associated with transcriptional repression of homeotic genes, as well as gene transcription activating effects. Particularly in cancer, PRCs have been found to misregulate gene expression, not only depending on the function of the whole PRCs, but also through their separate subunits. In this review, we focused especially on the recent findings in the transcriptional regulation of PRCs, the oncogenic and tumor-suppressive roles of PcG proteins, and the research progress of inhibitors targeting PRCs.

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Strutt, H., i R. Paro. "The polycomb group protein complex of Drosophila melanogaster has different compositions at different target genes." Molecular and Cellular Biology 17, nr 12 (grudzień 1997): 6773–83. http://dx.doi.org/10.1128/mcb.17.12.6773.

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In Drosophila the Polycomb group genes are required for the long-term maintenance of the repressed state of many developmental regulatory genes. Their gene products are thought to function in a common multimeric complex that associates with Polycomb group response elements (PREs) in target genes and regulates higher-order chromatin structure. We show that the chromodomain of Polycomb is necessary for protein-protein interactions within a Polycomb-Polyhomeotic complex. In addition, Posterior Sex Combs protein coimmunoprecipitates Polycomb and Polyhomeotic, indicating that they are members of a common multimeric protein complex. Immunoprecipitation experiments using in vivo cross-linked chromatin indicate that these three Polycomb group proteins are associated with identical regulatory elements of the selector gene engrailed in tissue culture cells. Polycomb, Polyhomeotic, and Posterior Sex Combs are, however, differentially distributed on regulatory sequences of the engrailed-related gene invected. This suggests that there may be multiple different Polycomb group protein complexes which function at different target sites. Furthermore, Polyhomeotic and Posterior Sex Combs are also associated with expressed genes. Polyhomeotic and Posterior Sex Combs may participate in a more general transcriptional mechanism that causes modulated gene repression, whereas the inclusion of Polycomb protein in the complex at PREs leads to stable silencing.

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Meseure, D., S. Vacher, M. Trassard, K. Drak Alsibai, C. Le Ray, C. Régnier, F. Lerebours, R. Le Scodan, R. Lidereau i I. Bièche. "Rôles du complexe répresseur Polycomb EZH2/CBX7 et du long ARN non codant ANRIL dans l’induction des mécanismes de silencing épigénétique. Implications thérapeutiques potentielles dans les carcinomes mammaires de type triple négatif". Annales de Pathologie 31, nr 5 (listopad 2011): S125. http://dx.doi.org/10.1016/j.annpat.2011.09.021.

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Ali, Janann Y., i Welcome Bender. "Cross-Regulation among the Polycomb Group Genes in Drosophila melanogaster". Molecular and Cellular Biology 24, nr 17 (1.09.2004): 7737–47. http://dx.doi.org/10.1128/mcb.24.17.7737-7747.2004.

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ABSTRACT Genes of the Polycomb group in Drosophila melanogaster function as long-term transcriptional repressors. A few members of the group encode proteins found in two evolutionarily conserved chromatin complexes, Polycomb repressive complex 1 (PRC1) and the ESC-E(Z) complex. The majority of the group, lacking clear biochemical functions, might be indirect regulators. The transcript levels of seven Polycomb group genes were assayed in embryos mutant for various other genes in the family. Three Polycomb group genes were identified as upstream positive regulators of the core components of PRC1. There is also negative feedback regulation of some PRC1 core components by other PRC1 genes. Finally, there is positive regulation of PRC1 components by the ESC-E(Z) complex. These multiple pathways of cross-regulation help to explain the large size of the Polycomb group family of genes, but they complicate the genetic analysis of any single member.

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Zhou, Haining, Chad B. Stein, Tiasha A. Shafiq, Gergana Shipkovenska, Marian Kalocsay, Joao A. Paulo, Jiuchun Zhang i in. "Rixosomal RNA degradation contributes to silencing of Polycomb target genes". Nature 604, nr 7904 (30.03.2022): 167–74. http://dx.doi.org/10.1038/s41586-022-04598-0.

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AbstractPolycomb repressive complexes 1 and 2 (PRC1 and PRC2) are histone-modifying and -binding complexes that mediate the formation of facultative heterochromatin and are required for silencing of developmental genes and maintenance of cell fate1–3. Multiple pathways of RNA decay work together to establish and maintain heterochromatin in fission yeast, including a recently identified role for a conserved RNA-degradation complex known as the rixosome or RIX1 complex4–6. Whether RNA degradation also has a role in the stability of mammalian heterochromatin remains unknown. Here we show that the rixosome contributes to silencing of many Polycomb targets in human cells. The rixosome associates with human PRC complexes and is enriched at promoters of Polycomb target genes. Depletion of either the rixosome or Polycomb results in accumulation of paused and elongating RNA polymerase at Polycomb target genes. We identify point mutations in the RING1B subunit of PRC1 that disrupt the interaction between PRC1 and the rixosome and result in diminished silencing, suggesting that direct recruitment of the rixosome to chromatin is required for silencing. Finally, we show that the RNA endonuclease and kinase activities of the rixosome and the downstream XRN2 exoribonuclease, which degrades RNAs with 5′ monophosphate groups generated by the rixosome, are required for silencing. Our findings suggest that rixosomal degradation of nascent RNA is conserved from fission yeast to human, with a primary role in RNA degradation at facultative heterochromatin in human cells.

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MA, Ke-Xue, i Xing-Zi XI. "Polycomb group protein complexes". Hereditas (Beijing) 31, nr 10 (22.12.2009): 977–81. http://dx.doi.org/10.3724/sp.j.1005.2009.00977.

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Gahan, James M., Fabian Rentzsch i Christine E. Schnitzler. "The genetic basis for PRC1 complex diversity emerged early in animal evolution". Proceedings of the National Academy of Sciences 117, nr 37 (31.08.2020): 22880–89. http://dx.doi.org/10.1073/pnas.2005136117.

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Polycomb group proteins are essential regulators of developmental processes across animals. Despite their importance, studies on Polycomb are often restricted to classical model systems and, as such, little is known about the evolution of these important chromatin regulators. Here we focus on Polycomb Repressive Complex 1 (PRC1) and trace the evolution of core components of canonical and non-canonical PRC1 complexes in animals. Previous work suggested that a major expansion in the number of PRC1 complexes occurred in the vertebrate lineage. We show that the expansion of the Polycomb Group RING Finger (PCGF) protein family, an essential step for the establishment of the large diversity of PRC1 complexes found in vertebrates, predates the bilaterian–cnidarian ancestor. This means that the genetic repertoire necessary to form all major vertebrate PRC1 complexes emerged early in animal evolution, over 550 million years ago. We further show that PCGF5, a gene conserved in cnidarians and vertebrates but lost in all other studied groups, is expressed in the nervous system in the sea anemone Nematostella vectensis, similar to its mammalian counterpart. Together this work provides a framework for understanding the evolution of PRC1 complex diversity and it establishes Nematostella as a promising model system in which the functional ramifications of this diversification can be further explored.

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Chittock, Emily C., Sebastian Latwiel, Thomas C. R. Miller i Christoph W. Müller. "Molecular architecture of polycomb repressive complexes". Biochemical Society Transactions 45, nr 1 (8.02.2017): 193–205. http://dx.doi.org/10.1042/bst20160173.

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The polycomb group (PcG) proteins are a large and diverse family that epigenetically repress the transcription of key developmental genes. They form three broad groups of polycomb repressive complexes (PRCs) known as PRC1, PRC2 and Polycomb Repressive DeUBiquitinase, each of which modifies and/or remodels chromatin by distinct mechanisms that are tuned by having variable compositions of core and accessory subunits. Until recently, relatively little was known about how the various PcG proteins assemble to form the PRCs; however, studies by several groups have now allowed us to start piecing together the PcG puzzle. Here, we discuss some highlights of recent PcG structures and the insights they have given us into how these complexes regulate transcription through chromatin.

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Lund, Anders H., i Maarten van Lohuizen. "Polycomb complexes and silencing mechanisms". Current Opinion in Cell Biology 16, nr 3 (czerwiec 2004): 239–46. http://dx.doi.org/10.1016/j.ceb.2004.03.010.

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Schwartz, Yuri B., i Vincenzo Pirrotta. "Polycomb complexes and epigenetic states". Current Opinion in Cell Biology 20, nr 3 (czerwiec 2008): 266–73. http://dx.doi.org/10.1016/j.ceb.2008.03.002.

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Blastyák, András, Rakesh K. Mishra, Francois Karch i Henrik Gyurkovics. "Efficient and Specific Targeting of Polycomb Group Proteins Requires Cooperative Interaction between Grainyhead and Pleiohomeotic". Molecular and Cellular Biology 26, nr 4 (15.02.2006): 1434–44. http://dx.doi.org/10.1128/mcb.26.4.1434-1444.2006.

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ABSTRACT Specific targeting of the protein complexes formed by the Polycomb group of proteins is critically required to maintain the inactive state of a group of developmentally regulated genes. Although the role of DNA binding proteins in this process has been well established, it is still not understood how these proteins target the Polycomb complexes specifically to their response elements. Here we show that the grainyhead gene, which encodes a DNA binding protein, interacts with one such Polycomb response element of the bithorax complex. Grainyhead binds to this element in vitro. Moreover, grainyhead interacts genetically with pleiohomeotic in a transgene-based, pairing-dependent silencing assay. Grainyhead also interacts with Pleiohomeotic in vitro, which facilitates the binding of both proteins to their respective target DNAs. Such interactions between two DNA binding proteins could provide the basis for the cooperative assembly of a nucleoprotein complex formed in vitro. Based on these results and the available data, we propose that the role of DNA binding proteins in Polycomb group-dependent silencing could be described by a model very similar to that of an enhanceosome, wherein the unique arrangement of protein-protein interaction modules exposed by the cooperatively interacting DNA binding proteins provides targeting specificity.

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Bakhshinyan, David, Ashley A. Adile, Chitra Venugopal i Sheila K. Singh. "Bmi1 – A Path to Targeting Cancer Stem Cells". European Oncology & Haematology 13, nr 02 (2017): 147. http://dx.doi.org/10.17925/eoh.2017.13.02.147.

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The Polycomb group (PcG) genes encode for proteins comprising two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). Although the initial discovery of PcG genes was made in Drosophila, as transcriptional repressors of homeotic (HOX) genes. Polycomb repressive complexes have been since implicated in regulating a wide range of cellular processes, including differentiation and self-renewal in normal and cancer stem cells. Bmi1, a subunit of PRC1, has been long implicated in driving self-renewal, the key property of stem cells. Subsequent studies showing upregulation of Bmi1 in several cancers correlated with increased aggressiveness, radioresistance and metastatic potential, provided rationale for development of targeted therapies against Bmi1. Although Bmi1 activity can be reduced through transcriptional, post-transcriptional and post-translational regulation, to date, the most promising approach has been through small molecule inhibitors targeting Bmi1 activity. The post-translational targeting of Bmi1 in colorectal carcinoma, lung adenocarcinoma, multiple myeloma and medulloblastoma have led to significant reduction of self-renewal capacity of cancer stem cells, leading to slower tumour progression and reduced extent of metastatic spread. Further value of Bmi1 targeting in cancer can be established through trials evaluating the combinatorial effect of Bmi1 inhibition with current ‘gold standard’ therapies.

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Wotton, D., i J. C. Merrill. "Pc2 and SUMOylation". Biochemical Society Transactions 35, nr 6 (23.11.2007): 1401–4. http://dx.doi.org/10.1042/bst0351401.

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Polycomb proteins are key regulators of transcription in metazoan organisms. Recent work has shed light on the nature of the polycomb protein complexes in flies and mammalian cells. Multiple enzymatic activities have been shown to associate with polycomb complexes, including histone methyltransferase, histone deacetylase and ubiquitination activities, which are primarily directed towards the modification of chromatin structure. In addition to these chromatin-based functions, other potential roles for polycomb proteins exist. Here, we present a comparison of vertebrate Pc2 (polycomb 2 protein) homologues, and review the known functions of the mammalian Pc2 focusing on its role as a SUMO (small ubiquitin-related modifier) E3 ligase. Pc2 is an E3 for several SUMO substrates, but still appears to have a more limited repertoire than other SUMO E3s, perhaps due to its association with polycomb complexes. One possibility is that Pc2 represents a relatively specialized polycomb protein, which has additional functions to those associated with other mammalian Pc (polycomb protein) paralogues.

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De, Sandip, Natalie D. Gehred, Miki Fujioka, Fountane W. Chan, James B. Jaynes i Judith A. Kassis. "Defining the Boundaries of Polycomb Domains in Drosophila". Genetics 216, nr 3 (18.09.2020): 689–700. http://dx.doi.org/10.1534/genetics.120.303642.

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Polycomb group (PcG) proteins are an important group of transcriptional repressors that act by modifying chromatin. PcG target genes are covered by the repressive chromatin mark H3K27me3. Polycomb repressive complex 2 (PRC2) is a multiprotein complex that is responsible for generating H3K27me3. In Drosophila, PRC2 is recruited by Polycomb Response Elements (PREs) and then trimethylates flanking nucleosomes, spreading the H3K27me3 mark over large regions of the genome, the “Polycomb domains.” What defines the boundary of a Polycomb domain? There is experimental evidence that insulators, PolII, and active transcription can all form the boundaries of Polycomb domains. Here we divide the boundaries of larval Polycomb domains into six different categories. In one category, genes are transcribed toward the Polycomb domain, where active transcription is thought to stop the spreading of H3K27me3. In agreement with this, we show that introducing a transcriptional terminator into such a transcription unit causes an extension of the Polycomb domain. Additional data suggest that active transcription of a boundary gene may restrict the range of enhancer activity of a Polycomb-regulated gene.

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Brockdorff, Neil. "Polycomb complexes in X chromosome inactivation". Philosophical Transactions of the Royal Society B: Biological Sciences 372, nr 1733 (25.09.2017): 20170021. http://dx.doi.org/10.1098/rstb.2017.0021.

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Identifying the critical RNA binding proteins (RBPs) that elicit Xist mediated silencing has been a key goal in X inactivation research. Early studies implicated the Polycomb proteins, a family of factors linked to one of two major multiprotein complexes, PRC1 and PRC2 (Wang 2001 Nat. Genet. 28 , 371–375 ( doi:10.1038/ng574 ); Silva 2003 Dev. Cell 4 , 481–495 ( doi:10.1016/S1534-5807(03)00068-6 ); de Napoles 2004 Dev. Cell 7 , 663–676 ( doi:10.1016/j.devcel.2004.10.005 ); Plath 2003 Science 300 , 131–135 ( doi:10.1126/science.1084274 )). PRC1 and PRC2 complexes catalyse specific histone post-translational modifications (PTMs), ubiquitylation of histone H2A at position lysine 119 (H2AK119u1) and methylation of histone H3 at position lysine 27 (H3K27me3), respectively, and accordingly, these modifications are highly enriched over the length of the inactive X chromosome (Xi). A key study proposed that PRC2 subunits bind directly to Xist RNA A-repeat element, a region located at the 5′ end of the transcript known to be required for Xist mediated silencing (Zhao 2008 Science 322 , 750–756 ( doi:10.1126/science.1163045 )). Subsequent recruitment of PRC1 was assumed to occur via recognition of PRC2 mediated H3K27me3 by the CBX subunit of PRC1, as has been shown to be the case at other Polycomb target loci (Cao 2002 Science 298 , 1039–1043 ( doi:10.1126/science.1076997 )). More recently, several reports have questioned aspects of the prevailing view, both in relation to the mechanism for Polycomb recruitment by Xist RNA and the contribution of the Polycomb pathway to Xist mediated silencing. In this article I provide an overview of our recent progress towards resolving these discrepancies. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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Schuettengruber, Bernd, i Giacomo Cavalli. "The DUBle Life of Polycomb Complexes". Developmental Cell 18, nr 6 (czerwiec 2010): 878–80. http://dx.doi.org/10.1016/j.devcel.2010.06.001.

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Dorafshan, Eshagh, Tatyana G. Kahn i Yuri B. Schwartz. "Hierarchical recruitment of Polycomb complexes revisited". Nucleus 8, nr 5 (3.09.2017): 496–505. http://dx.doi.org/10.1080/19491034.2017.1363136.

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Iwama, Atsushi. "Polycomb repressive complexes in hematological malignancies". Blood 130, nr 1 (6.07.2017): 23–29. http://dx.doi.org/10.1182/blood-2017-02-739490.

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Abstract The deregulation of polycomb repressive complexes (PRCs) has been reported in a number of hematological malignancies. These complexes exert oncogenic or tumor-suppressive functions depending on tumor type. These findings have revolutionized our understanding of the pathophysiology of hematological malignancies and the impact of deregulated epigenomes in tumor development and progression. The therapeutic targeting of PRCs is currently attracting increasing attention and being extensively examined in clinical studies, leading to new therapeutic strategies that may improve the outcomes of patients with hematological malignancies.

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Chiang, A., M. B. O'Connor, R. Paro, J. Simon i W. Bender. "Discrete Polycomb-binding sites in each parasegmental domain of the bithorax complex". Development 121, nr 6 (1.06.1995): 1681–89. http://dx.doi.org/10.1242/dev.121.6.1681.

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The Polycomb protein of Drosophila melanogaster maintains the segmental expression limits of the homeotic genes in the bithorax complex. Polycomb-binding sites within the bithorax complex were mapped by immunostaining of salivary gland polytene chromosomes. Polycomb bound to four DNA fragments, one in each of four successive parasegmental regulatory regions. These fragments correspond exactly to the ones that can maintain segmentally limited expression of a lacZ reporter gene. Thus, Polycomb acts directly on discrete multiple sites in bithorax regulatory DNA. Constructs combining fragments from different regulatory regions demonstrate that Polycomb-dependent maintenance elements can act on multiple pattern initiation elements, and that maintenance elements can work together. The cooperative action of maintenance elements may motivate the linear order of the bithorax complex.

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Hernández-Muñoz, Inmaculada, Panthea Taghavi, Coenraad Kuijl, Jacques Neefjes i Maarten van Lohuizen. "Association of BMI1 with Polycomb Bodies Is Dynamic and Requires PRC2/EZH2 and the Maintenance DNA Methyltransferase DNMT1". Molecular and Cellular Biology 25, nr 24 (15.12.2005): 11047–58. http://dx.doi.org/10.1128/mcb.25.24.11047-11058.2005.

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ABSTRACT Polycomb group (PcG) proteins are epigenetic chromatin modifiers involved in heritable gene repression. Two main PcG complexes have been characterized. Polycomb repressive complex 2 (PRC2) is thought to be involved in the initiation of gene silencing, whereas Polycomb repressive complex 1 (PRC1) is implicated in the stable maintenance of gene repression. Here, we investigate the kinetic properties of the binding of one of the PRC1 core components, BMI1, with PcG bodies. PcG bodies are unique nuclear structures located on regions of pericentric heterochromatin, found to be the site of accumulation of PcG complexes in different cell lines. We report the presence of at least two kinetically different pools of BMI1, a highly dynamic and a less dynamic fraction, which may reflect BMI1 pools with different binding capacities to these stable heterochromatin domains. Interestingly, PRC2 members EED and EZH2 appear to be essential for BMI1 recruitment to the PcG bodies. Furthermore, we demonstrate that the maintenance DNA methyltransferase DNMT1 is necessary for proper PcG body assembly independent of DNMT-associated histone deacetylase activity. Together, these results provide new insights in the mechanism for regulation of chromatin silencing by PcG proteins and suggest a highly regulated recruitment of PRC1 to chromatin.

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Vijayanathan, Mallika, María Guadalupe Trejo-Arellano i Iva Mozgová. "Polycomb Repressive Complex 2 in Eukaryotes—An Evolutionary Perspective". Epigenomes 6, nr 1 (17.01.2022): 3. http://dx.doi.org/10.3390/epigenomes6010003.

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Polycomb repressive complex 2 (PRC2) represents a group of evolutionarily conserved multi-subunit complexes that repress gene transcription by introducing trimethylation of lysine 27 on histone 3 (H3K27me3). PRC2 activity is of key importance for cell identity specification and developmental phase transitions in animals and plants. The composition, biochemistry, and developmental function of PRC2 in animal and flowering plant model species are relatively well described. Recent evidence demonstrates the presence of PRC2 complexes in various eukaryotic supergroups, suggesting conservation of the complex and its function. Here, we provide an overview of the current understanding of PRC2-mediated repression in different representatives of eukaryotic supergroups with a focus on the green lineage. By comparison of PRC2 in different eukaryotes, we highlight the possible common and diverged features suggesting evolutionary implications and outline emerging questions and directions for future research of polycomb repression and its evolution.

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Ngubo, Mzwanele, Fereshteh Moradi, Caryn Y. Ito i William L. Stanford. "Tissue-Specific Tumour Suppressor and Oncogenic Activities of the Polycomb-like Protein MTF2". Genes 14, nr 10 (27.09.2023): 1879. http://dx.doi.org/10.3390/genes14101879.

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The Polycomb repressive complex 2 (PRC2) is a conserved chromatin-remodelling complex that catalyses the trimethylation of histone H3 lysine 27 (H3K27me3), a mark associated with gene silencing. PRC2 regulates chromatin structure and gene expression during organismal and tissue development and tissue homeostasis in the adult. PRC2 core subunits are associated with various accessory proteins that modulate its function and recruitment to target genes. The multimeric composition of accessory proteins results in two distinct variant complexes of PRC2, PRC2.1 and PRC2.2. Metal response element-binding transcription factor 2 (MTF2) is one of the Polycomb-like proteins (PCLs) that forms the PRC2.1 complex. MTF2 is highly conserved, and as an accessory subunit of PRC2, it has important roles in embryonic stem cell self-renewal and differentiation, development, and cancer progression. Here, we review the impact of MTF2 in PRC2 complex assembly, catalytic activity, and spatiotemporal function. The emerging paradoxical evidence suggesting that MTF2 has divergent roles as either a tumour suppressor or an oncogene in different tissues merits further investigations. Altogether, our review illuminates the context-dependent roles of MTF2 in Polycomb group (PcG) protein-mediated epigenetic regulation. Its impact on disease paves the way for a deeper understanding of epigenetic regulation and novel therapeutic strategies.

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Schubert, Daniel. "Evolution of Polycomb-group function in the green lineage". F1000Research 8 (8.03.2019): 268. http://dx.doi.org/10.12688/f1000research.16986.1.

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Epigenetic gene regulation ensures the mitotically or meiotically stable heritability (or both) of gene expression or protein activity states and maintains repetitive element repression and cellular identities. The repressive Polycomb-group (PcG) proteins consist of several large complexes that control cellular memory by acting on chromatin and are antagonized by the Trithorax-group proteins. Especially, Polycomb repressive complex 2 (PRC2) is highly conserved in plants and animals but its function in unicellular eukaryotes and during land plant evolution is less understood. Additional PcG complexes and associated proteins are only partially conserved and have evolved in a lineage-specific manner. In this review, I will focus on recent advances in the understanding of PcG function in the green lineage and its contribution to land plant evolution.

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Ng, Joyce, Craig M. Hart, Kelly Morgan i Jeffrey A. Simon. "A Drosophila ESC-E(Z) Protein Complex Is Distinct from Other Polycomb Group Complexes and Contains Covalently Modified ESC". Molecular and Cellular Biology 20, nr 9 (1.05.2000): 3069–78. http://dx.doi.org/10.1128/mcb.20.9.3069-3078.2000.

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ABSTRACT The extra sex combs (ESC) and Enhancer of zeste [E(Z)] proteins, members of the Polycomb group (PcG) of transcriptional repressors, interact directly and are coassociated in fly embryos. We report that these two proteins are components of a 600-kDa complex in embryos. Using gel filtration and affinity chromatography, we show that this complex is biochemically distinct from previously described complexes containing the PcG proteins Polyhomeotic, Polycomb, and Sex comb on midleg. In addition, we present evidence that ESC is phosphorylated in vivo and that this modified ESC is preferentially associated in the complex with E(Z). Modified ESC accumulates between 2 and 6 h of embryogenesis, which is the developmental time whenesc function is first required. We find that mutations inE(z) reduce the ratio of modified to unmodified ESC in vivo. We have also generated germ line transformants that express ESC proteins bearing site-directed mutations that disrupt ESC-E(Z) binding in vitro. These mutant ESC proteins fail to provideesc function, show reduced levels of modification in vivo, and are still assembled into complexes. Taken together, these results suggest that ESC phosphorylation normally occurs after assembly into ESC-E(Z) complexes and that it contributes to the function or regulation of these complexes. We discuss how biochemically separable ESC-E(Z) and PC-PH complexes might work together to provide PcG repression.

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Tie, Feng, Carl A. Stratton, Rebeccah L. Kurzhals i Peter J. Harte. "The N Terminus of Drosophila ESC Binds Directly to Histone H3 and Is Required for E(Z)-Dependent Trimethylation of H3 Lysine 27". Molecular and Cellular Biology 27, nr 6 (8.01.2007): 2014–26. http://dx.doi.org/10.1128/mcb.01822-06.

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ABSTRACT Polycomb group proteins mediate heritable transcriptional silencing and function through multiprotein complexes that methylate and ubiquitinate histones. The 600-kDa E(Z)/ESC complex, also known as Polycomb repressive complex 2 (PRC2), specifically methylates histone H3 lysine 27 (H3 K27) through the intrinsic histone methyltransferase (HMTase) activity of the E(Z) SET domain. By itself, E(Z) exhibits no detectable HMTase activity and requires ESC for methylation of H3 K27. The molecular basis for this requirement is unknown. ESC binds directly, via its C-terminal WD repeats (β-propeller domain), to E(Z). Here, we show that the N-terminal region of ESC that precedes its β-propeller domain interacts directly with histone H3, thereby physically linking E(Z) to its substrate. We show that when expressed in stable S2 cell lines, an N-terminally truncated ESC (FLAG-ESC61-425), like full-length ESC, is incorporated into complexes with E(Z) and binds to a Ubx Polycomb response element in a chromatin immunoprecipitation assay. However, incorporation of this N-terminally truncated ESC into E(Z) complexes prevents trimethylation of histone H3 by E(Z). We also show that a closely related Drosophila melanogaster paralog of ESC, ESC-like (ESCL), and the mammalian homolog of ESC, EED, also interact with histone H3 via their N termini, indicating that the interaction of ESC with histone H3 is evolutionarily conserved, reflecting its functional importance. Our data suggest that one of the roles of ESC (and ESCL and EED) in PRC2 complexes is to enable E(Z) to utilize histone H3 as a substrate by physically linking enzyme and substrate.

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Loh, Chet H., i Gert Jan C. Veenstra. "The Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development". Epigenomes 6, nr 3 (12.08.2022): 23. http://dx.doi.org/10.3390/epigenomes6030023.

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Embryonic development is a highly intricate and complex process. Different regulatory mechanisms cooperatively dictate the fate of cells as they progress from pluripotent stem cells to terminally differentiated cell types in tissues. A crucial regulator of these processes is the Polycomb Repressive Complex 2 (PRC2). By catalyzing the mono-, di-, and tri-methylation of lysine residues on histone H3 tails (H3K27me3), PRC2 compacts chromatin by cooperating with Polycomb Repressive Complex 1 (PRC1) and represses transcription of target genes. Proteomic and biochemical studies have revealed two variant complexes of PRC2, namely PRC2.1 which consists of the core proteins (EZH2, SUZ12, EED, and RBBP4/7) interacting with one of the Polycomb-like proteins (MTF2, PHF1, PHF19), and EPOP or PALI1/2, and PRC2.2 which contains JARID2 and AEBP2 proteins. MTF2 and JARID2 have been discovered to have crucial roles in directing and recruiting PRC2 to target genes for repression in embryonic stem cells (ESCs). Following these findings, recent work in the field has begun to explore the roles of different PRC2 variant complexes during different stages of embryonic development, by examining molecular phenotypes of PRC2 mutants in both in vitro (2D and 3D differentiation) and in vivo (knock-out mice) assays, analyzed with modern single-cell omics and biochemical assays. In this review, we discuss the latest findings that uncovered the roles of different PRC2 proteins during cell-fate and lineage specification and extrapolate these findings to define a developmental roadmap for different flavors of PRC2 regulation during mammalian embryonic development.

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Tillib, Sergei, Svetlana Petruk, Yurii Sedkov, Alexander Kuzin, Miki Fujioka, Tadaatsu Goto i Alexander Mazo. "Trithorax- and Polycomb-Group Response Elements within an Ultrabithorax Transcription Maintenance Unit Consist of Closely Situated but Separable Sequences". Molecular and Cellular Biology 19, nr 7 (1.07.1999): 5189–202. http://dx.doi.org/10.1128/mcb.19.7.5189.

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ABSTRACT In Drosophila, two classes of genes, thetrithorax group and the Polycomb group, are required in concert to maintain gene expression by regulating chromatin structure. We have identified Trithorax protein (TRX) binding elements within the bithorax complex and have found that within thebxd/pbx regulatory region these elements are functionally relevant for normal expression patterns in embryos and confer TRX binding in vivo. TRX was localized to three closely situated sites within a 3-kb chromatin maintenance unit with a modular structure. Results of an in vivo analysis showed that these DNA fragments (each ∼400 bp) contain both TRX- and Polycomb-group response elements (TREs and PREs) and that in the context of the endogenousUltrabithorax gene, all of these elements are essential for proper maintenance of expression in embryos. Dissection of one of these maintenance modules showed that TRX- and Polycomb-group responsiveness is conferred by neighboring but separable DNA sequences, suggesting that independent protein complexes are formed at their respective response elements. Furthermore, we have found that the activity of this TRE requires a sequence (∼90 bp) which maps to within several tens of base pairs from the closest neighboring PRE and that the PRE activity in one of the elements may require a binding site for PHO, the protein product of the Polycomb-group genepleiohomeotic. Our results show that long-range maintenance of Ultrabithorax expression requires a complex element composed of cooperating modules, each capable of interacting with both positive and negative chromatin regulators.

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Lonie, A., R. D'Andrea, R. Paro i R. Saint. "Molecular characterisation of the Polycomblike gene of Drosophila melanogaster, a trans-acting negative regulator of homeotic gene expression". Development 120, nr 9 (1.09.1994): 2629–36. http://dx.doi.org/10.1242/dev.120.9.2629.

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The Polycomblike gene of Drosophila melanogaster, a member of the Polycomb Group of genes, is required for the correct spatial expression of the homeotic genes of the Antennapaedia and Bithorax Complexes. Mutations in Polycomb Group genes result in ectopic homeotic gene expression, indicating that Polycomb Group proteins maintain the transcriptional repression of specific homeotic genes in specific tissues during development. We report here the isolation and molecular characterisation of the Polycomblike gene. The Polycomblike transcript encodes an 857 amino acid protein with no significant homology to other proteins. Antibodies raised against the product of this open reading frame were used to show that the Polycomblike protein is found in all nuclei during embryonic development. Antibody staining also revealed that the Polycomblike protein is found on larval salivary gland polytene chromosomes at about 100 specific loci, the same loci to which the Polycomb and polyhomeotic proteins, two other Polycomb Group proteins, are found. These data add further support for a model in which Polycomb Group proteins form multimeric protein complexes at specific chromosomal loci to repress transcription at those loci.

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Sparavier, Aleksandra, i Luciano Di Croce. "Polycomb complexes in MLL–AF9-related leukemias". Current Opinion in Genetics & Development 75 (sierpień 2022): 101920. http://dx.doi.org/10.1016/j.gde.2022.101920.

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Bischof, Sylvain. "An open EAR for polycomb repressive complexes". Plant Cell 33, nr 8 (1.06.2021): 2517–18. http://dx.doi.org/10.1093/plcell/koab156.

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Di Carlo, Valerio, Ivano Mocavini i Luciano Di Croce. "Polycomb complexes in normal and malignant hematopoiesis". Journal of Cell Biology 218, nr 1 (19.10.2018): 55–69. http://dx.doi.org/10.1083/jcb.201808028.

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Epigenetic mechanisms are crucial for sustaining cell type–specific transcription programs. Among the distinct factors, Polycomb group (PcG) proteins are major negative regulators of gene expression in mammals. These proteins play key roles in regulating the proliferation, self-renewal, and differentiation of stem cells. During hematopoietic differentiation, many PcG proteins are fundamental for proper lineage commitment, as highlighted by the fact that a lack of distinct PcG proteins results in embryonic lethality accompanied by differentiation biases. Correspondingly, proteins of these complexes are frequently dysregulated in hematological diseases. In this review, we present an overview of the role of PcG proteins in normal and malignant hematopoiesis, focusing on the compositional complexity of PcG complexes, and we briefly discuss the ongoing clinical trials for drugs targeting these factors.

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Wang, Liangjun, J. Lesley Brown, Ru Cao, Yi Zhang, Judith A. Kassis i Richard S. Jones. "Hierarchical Recruitment of Polycomb Group Silencing Complexes". Molecular Cell 14, nr 5 (czerwiec 2004): 637–46. http://dx.doi.org/10.1016/j.molcel.2004.05.009.

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Kerppola, Tom K. "Polycomb group complexes – many combinations, many functions". Trends in Cell Biology 19, nr 12 (grudzień 2009): 692–704. http://dx.doi.org/10.1016/j.tcb.2009.10.001.

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Kim, S. Y., S. W. Paylor, T. Magnuson i A. Schumacher. "Juxtaposed Polycomb complexes co-regulate vertebral identity". Development 133, nr 24 (15.11.2006): 4957–68. http://dx.doi.org/10.1242/dev.02677.

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Tie, F., T. Furuyama, J. Prasad-Sinha, E. Jane i P. J. Harte. "The Drosophila Polycomb Group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3". Development 128, nr 2 (15.01.2001): 275–86. http://dx.doi.org/10.1242/dev.128.2.275.

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The Drosophila Polycomb Group (PcG) proteins are required for stable long term transcriptional silencing of the homeotic genes. Among PcG genes, esc is unique in being critically required for establishment of PcG-mediated silencing during early embryogenesis, but not for its subsequent maintenance throughout development. We previously showed that ESC is physically associated in vivo with the PcG protein E(Z). We report here that ESC, together with E(Z), is present in a 600 kDa complex that is distinct from complexes containing other PcG proteins. We have purified this ESC complex and show that it also contains the histone deacetylase RPD3 and the histone-binding protein p55, which is also a component of the chromatin remodeling complex NURF and the chromatin assembly complex CAF-1. The association of ESC and E(Z) with p55 and RPD3 is conserved in mammals. We show that RPD3 is required for silencing mediated by a Polycomb response element (PRE) in vivo and that E(Z) and RPD3 are bound to the Ubx PRE in vivo, suggesting that they act directly at the PRE. We propose that histone deacetylation by this complex is a prerequisite for establishment of stable long-term silencing by other continuously required PcG complexes.

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Lo, Stanley M., Nitin K. Ahuja i Nicole J. Francis. "Polycomb Group Protein Suppressor 2 of Zeste Is a Functional Homolog of Posterior Sex Combs". Molecular and Cellular Biology 29, nr 2 (3.11.2008): 515–25. http://dx.doi.org/10.1128/mcb.01044-08.

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ABSTRACT The Drosophila melanogaster Polycomb group protein Posterior Sex Combs is a component of Polycomb repressive complex 1 and is central to Polycomb group-mediated silencing. A related Polycomb group gene, Suppressor 2 of zeste, is thought to be partially redundant in function. The two proteins share a small region of homology but also contain regions of unconserved sequences. Here we report a biochemical characterization of Suppressor 2 of zeste. Like Posterior Sex Combs, Suppressor 2 of zeste binds DNA, compacts chromatin, and inhibits chromatin remodeling. Interestingly, the regions of the two proteins responsible for these activities lack sequence homology. Suppressor 2 of zeste can also replace Posterior Sex Combs in a functional complex with other Polycomb group proteins, but unlike with their biochemical activities, complex formation is mediated by the region of Suppressor 2 of zeste that is homologous to that of Posterior Sex Combs. Our results establish Suppressor 2 of zeste as a functional homolog of Posterior Sex Combs and suggest that the two proteins operate via similar molecular mechanisms.

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Yan, Bowen, Yanpeng Lv, Chunyu Zhao i Xiaoxue Wang. "Knowing When to Silence: Roles of Polycomb-Group Proteins in SAM Maintenance, Root Development, and Developmental Phase Transition". International Journal of Molecular Sciences 21, nr 16 (15.08.2020): 5871. http://dx.doi.org/10.3390/ijms21165871.

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Polycomb repressive complex 1 (PRC1) and PRC2 are the major complexes composed of polycomb-group (PcG) proteins in plants. PRC2 catalyzes trimethylation of lysine 27 on histone 3 to silence target genes. Like Heterochromatin Protein 1/Terminal Flower 2 (LHP1/TFL2) recognizes and binds to H3K27me3 generated by PRC2 activities and enrolls PRC1 complex to further silence the chromatin through depositing monoubiquitylation of lysine 119 on H2A. Mutations in PcG genes display diverse developmental defects during shoot apical meristem (SAM) maintenance and differentiation, seed development and germination, floral transition, and so on so forth. PcG proteins play essential roles in regulating plant development through repressing gene expression. In this review, we are focusing on recent discovery about the regulatory roles of PcG proteins in SAM maintenance, root development, embryo development to seedling phase transition, and vegetative to reproductive phase transition.

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LaJeunesse, D., i A. Shearn. "E(z): a polycomb group gene or a trithorax group gene?" Development 122, nr 7 (1.07.1996): 2189–97. http://dx.doi.org/10.1242/dev.122.7.2189.

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The products of the Polycomb group of genes are cooperatively involved in repressing expression of homeotic selector genes outside of their appropriate anterior/posterior boundaries. Loss of maternal and/or zygotic function of Polycomb group genes results in the ectopic expression of both Antennapedia Complex and Bithorax Complex genes. The products of the trithorax group of genes are cooperatively involved in maintaining active expression of homeotic selector genes within their appropriate anterior/posterior boundaries. Loss of maternal and/or zygotic function of trithorax group genes results in reduced expression of both Antennapedia Complex and Bithorax Complex genes. Although Enhancer of zeste has been classified as a member of the Polycomb group, in this paper we show that Enhancer of zeste can also be classified as a member of the trithorax group. The requirement for Enhancer of zeste activity as either a trithorax group or Polycomb group gene depends on the homeotic selector gene locus as well as on spatial and temporal cues.

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Sewalt, Richard G. A. B., Monika Lachner, Mark Vargas, Karien M. Hamer, Jan L. den Blaauwen, Thijs Hendrix, Martin Melcher, Dieter Schweizer, Thomas Jenuwein i Arie P. Otte. "Selective Interactions between Vertebrate Polycomb Homologs and the SUV39H1 Histone Lysine Methyltransferase Suggest that Histone H3-K9 Methylation Contributes to Chromosomal Targeting of Polycomb Group Proteins". Molecular and Cellular Biology 22, nr 15 (1.08.2002): 5539–53. http://dx.doi.org/10.1128/mcb.22.15.5539-5553.2002.

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ABSTRACT Polycomb group (PcG) proteins form multimeric chromatin-associated protein complexes that are involved in heritable repression of gene activity. Two distinct human PcG complexes have been characterized. The EED/EZH2 PcG complex utilizes histone deacetylation to repress gene activity. The HPC/HPH PcG complex contains the HPH, RING1, BMI1, and HPC proteins. Here we show that vertebrate Polycomb homologs HPC2 and XPc2, but not M33/MPc1, interact with the histone lysine methyltransferase (HMTase) SUV39H1 both in vitro and in vivo. We further find that overexpression of SUV39H1 induces selective nuclear relocalization of HPC/HPH PcG proteins but not of the EED/EZH2 PcG proteins. This SUV39H1-dependent relocalization concentrates the HPC/HPH PcG proteins to the large pericentromeric heterochromatin domains (1q12) on human chromosome 1. Within these PcG domains we observe increased H3-K9 methylation. Finally, we show that H3-K9 HMTase activity is associated with endogenous HPC2. Our findings suggest a role for the SUV39H1 HMTase and histone H3-K9 methylation in the targeting of human HPC/HPH PcG proteins to modified chromatin structures.

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40

Boulay, Gaylor, Claire Rosnoblet, Cateline Guérardel, Pierre-Olivier Angrand i Dominique Leprince. "Functional characterization of human Polycomb-like 3 isoforms identifies them as components of distinct EZH2 protein complexes". Biochemical Journal 434, nr 2 (11.02.2011): 333–42. http://dx.doi.org/10.1042/bj20100944.

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PcG (Polycomb group) proteins are conserved transcriptional repressors essential to regulate cell fate and to maintain epigenetic cellular memory. They work in concert through two main families of chromatin-modifying complexes, PRC1 (Polycomb repressive complex 1) and PRC2–4. In Drosophila, PRC2 contains the H3K27 histone methyltransferase E(Z) whose trimethylation activity towards PcG target genes is stimulated by PCL (Polycomb-like). In the present study, we have examined hPCL3, one of its three human paralogues. Through alternative splicing, hPCL3 encodes a long isoform, hPCL3L, containing an N-terminal TUDOR domain and two PHDs (plant homeodomains) and a smaller isoform, hPCL3S, lacking the second PHD finger (PHD2). By quantitative reverse transcription–PCR analyses, we showed that both isoforms are widely co-expressed at high levels in medulloblastoma. By co-immunoprecipitation analyses, we demonstrated that both isoforms interact with EZH2 through their common TUDOR domain. However, the hPCL3L-specific PHD2 domain, which is better conserved than PHD1 in the PCL family, is also involved in this interaction and implicated in the self-association of hPCL3L. Finally, we have demonstrated that both hPCL3 isoforms are physically associated with EZH2, but in different complexes. Our results provide the first evidence that the two hPCL3 isoforms belong to different complexes and raise important questions about their relative functions, particularly in tumorigenesis.

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Jullien, Pauline E., Aviva Katz, Moran Oliva, Nir Ohad i Frédéric Berger. "Polycomb Group Complexes Self-Regulate Imprinting of the Polycomb Group Gene MEDEA in Arabidopsis". Current Biology 16, nr 5 (marzec 2006): 486–92. http://dx.doi.org/10.1016/j.cub.2006.01.020.

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Wang, Liangjun, Neal Jahren, Ellen L. Miller, Carrie S. Ketel, Daniel R. Mallin i Jeffrey A. Simon. "Comparative Analysis of Chromatin Binding by Sex Comb on Midleg (SCM) and Other Polycomb Group Repressors at a Drosophila Hox Gene". Molecular and Cellular Biology 30, nr 11 (29.03.2010): 2584–93. http://dx.doi.org/10.1128/mcb.01451-09.

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ABSTRACT Sex Comb on Midleg (SCM) is a transcriptional repressor in the Polycomb group (PcG), but its molecular role in PcG silencing is not known. Although SCM can interact with Polycomb repressive complex 1 (PRC1) in vitro, biochemical studies have indicated that SCM is not a core constituent of PRC1 or PRC2. Nevertheless, SCM is just as critical for Drosophila Hox gene silencing as canonical subunits of these well-characterized PcG complexes. To address functional relationships between SCM and other PcG components, we have performed chromatin immunoprecipitation studies using cultured Drosophila Schneider line 2 (S2) cells and larval imaginal discs. We find that SCM associates with a Polycomb response element (PRE) upstream of the Ubx gene which also binds PRC1, PRC2, and the DNA-binding PcG protein Pleiohomeotic (PHO). However, SCM is retained at this Ubx PRE despite genetic disruption or knockdown of PHO, PRC1, or PRC2, suggesting that SCM chromatin targeting does not require prior association of these other PcG components. Chromatin immunoprecipitations (IPs) to test the consequences of SCM genetic disruption or knockdown revealed that PHO association is unaffected, but reduced levels of PRE-bound PRC2 and PRC1 were observed. We discuss these results in light of current models for recruitment of PcG complexes to chromatin targets.

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Boulay, Gaylor, Luisa Cironi, Sara P. Garcia, Shruthi Rengarajan, Yu-Hang Xing, Lukuo Lee, Mary E. Awad i in. "The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies". Life Science Alliance 4, nr 2 (23.12.2020): e202000808. http://dx.doi.org/10.26508/lsa.202000808.

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Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.

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Piunti, Andrea, Edwin R. Smith, Marc A. J. Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn A. Helmin, Caila A. Ryan i in. "CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism". Science Advances 5, nr 7 (lipiec 2019): eaax2887. http://dx.doi.org/10.1126/sciadv.aax2887.

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Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67’s interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene:CATACOMB(catalytic antagonist of Polycomb; official gene name:EZHIP). We mapCATACOMB’sinhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. AsCATACOMBexpression is regulated through DNA methylation/demethylation, we proposeCATACOMBas the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.

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45

German, Beatriz, i Leigh Ellis. "Polycomb Directed Cell Fate Decisions in Development and Cancer". Epigenomes 6, nr 3 (6.09.2022): 28. http://dx.doi.org/10.3390/epigenomes6030028.

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The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.

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46

Geng, Zhuangzhuang, i Zhonghua Gao. "Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms". International Journal of Molecular Sciences 21, nr 22 (14.11.2020): 8594. http://dx.doi.org/10.3390/ijms21228594.

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Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. This review summarizes new advancements regarding the composition of mammalian PRC1 and accompanying explanations of how diverse PRC1-associated proteins participate in distinct transcription regulation mechanisms.

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Hernández-Romero, Itzel Alejandra, i Victor Julian Valdes. "De Novo Polycomb Recruitment and Repressive Domain Formation". Epigenomes 6, nr 3 (22.08.2022): 25. http://dx.doi.org/10.3390/epigenomes6030025.

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Every cell of an organism shares the same genome; even so, each cellular lineage owns a different transcriptome and proteome. The Polycomb group proteins (PcG) are essential regulators of gene repression patterning during development and homeostasis. However, it is unknown how the repressive complexes, PRC1 and PRC2, identify their targets and elicit new Polycomb domains during cell differentiation. Classical recruitment models consider the pre-existence of repressive histone marks; still, de novo target binding overcomes the absence of both H3K27me3 and H2AK119ub. The CpG islands (CGIs), non-core proteins, and RNA molecules are involved in Polycomb recruitment. Nonetheless, it is unclear how de novo targets are identified depending on the physiological context and developmental stage and which are the leading players stabilizing Polycomb complexes at domain nucleation sites. Here, we examine the features of de novo sites and the accessory elements bridging its recruitment and discuss the first steps of Polycomb domain formation and transcriptional regulation, comprehended by the experimental reconstruction of the repressive domains through time-resolved genomic analyses in mammals.

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Chang, Y. L., B. O. King, M. O'Connor, A. Mazo i D. H. Huang. "Functional reconstruction of trans regulation of the Ultrabithorax promoter by the products of two antagonistic genes, trithorax and Polycomb." Molecular and Cellular Biology 15, nr 12 (grudzień 1995): 6601–12. http://dx.doi.org/10.1128/mcb.15.12.6601.

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Maintenance of the "on-off" state of Drosophila homeotic genes in Antennapedia and bithorax complexes requires activities of the trithorax and Polycomb groups of genes. To identify cis-acting sequences for functional reconstruction of regulation by both trithorax and Polycomb, we examined the expression patterns of several Ubx-lacZ transgenes that carry upstream fragments corresponding to a region of approximately 50 kb. A 14.5-kb fragment from the postbithorax/bithoraxoid region of Ultrabithorax exhibited proper regulation by both trithorax and Polycomb in the embryonic central nervous system. Using a Drosophila haploid cell line for transient expression, we found that trithorax or Polycomb can function independently through this upstream fragment to activate or repress the Ultrabithorax promoter, respectively. Studies of deletion mutants of trithorax and Polycomb demonstrated that trithorax-dependent activation requires the central zinc-binding domain, while Polycomb-dependent repression requires the intact chromodomain. In addition, trithorax-dependent activity can be abrogated by increasing the amount of Polycomb, suggesting a competitive interaction between the products of trithorax and Polycomb. Deletion analysis of this fragment demonstrated that a 440-bp fragment contains response elements for both trithorax and Polycomb. Furthermore, we showed that the integrity of the proximal promoter region is essential for trithorax-dependent activation, implicating a long-range interaction for promoter activation.

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Muller, J., S. Gaunt i P. A. Lawrence. "Function of the Polycomb protein is conserved in mice and flies". Development 121, nr 9 (1.09.1995): 2847–52. http://dx.doi.org/10.1242/dev.121.9.2847.

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A key aspect of determination--the acquisition and propagation of cell fates--is the initiation of patterns of selector gene expression and their maintenance in groups of cells as they divide and develop. In Drosophila, in those groups of cells where particular selector genes must remain inactive, it is the Polycomb-Group of genes that keep them silenced. Here we show that M33, a mouse homologue of the Drosophila Polycomb protein, can substitute for Polycomb in transgenic flies. Polycomb protein is thought to join with other Polycomb-Group proteins to build a complex that silences selector genes. Since members of this group of proteins have their homologues in mice, our results suggest that the molecular mechanism of cell determination is widely conserved.

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Costa, Silvia, i Caroline Dean. "Storing memories: the distinct phases of Polycomb-mediated silencing of Arabidopsis FLC". Biochemical Society Transactions 47, nr 4 (5.07.2019): 1187–96. http://dx.doi.org/10.1042/bst20190255.

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Abstract Polycomb-mediated epigenetic silencing is central to correct growth and development in higher eukaryotes. The evolutionarily conserved Polycomb repressive complex 2 (PRC2) transcriptionally silences target genes through a mechanism requiring the histone modification H3K27me3. However, we still do not fully understand what defines Polycomb targets, how their expression state is switched from epigenetically ON to OFF and how silencing is subsequently maintained through many cell divisions. An excellent system in which to dissect the sequence of events underlying an epigenetic switch is the Arabidopsis FLC locus. Exposure to cold temperatures progressively induces a PRC2-dependent switch in an increasing proportion of cells, through a mechanism that is driven by the local chromatin environment. Temporally distinct phases of this silencing mechanism have been identified. First, the locus is transcriptionally silenced in a process involving cold-induced antisense transcripts; second, nucleation at the first exon/intron boundary of a Polycomb complex containing cold-induced accessory proteins induces a metastable epigenetically silenced state; third, a Polycomb complex with a distinct composition spreads across the locus in a process requiring DNA replication to deliver long-term epigenetic silencing. Detailed understanding from this system is likely to provide mechanistic insights important for epigenetic silencing in eukaryotes generally.

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