Recruitment of Polycomb group complexes and their role in the dynamic regulation of cell fate choice

Polycomb group (PcG) protein complexes dynamically define cellular identity through the regulation of key developmental genes. Important advances in the PcG field have come from genome-wide mapping studies in a variety of tissues and cell types that have analyzed PcG protein complexes, their associated histone marks and putative mechanisms of PcG protein recruitment. We review how these analyses have contributed to our understanding of PcG protein complex targeting to chromatin and consider the importance of diverse PcG protein complex composition for gene regulation. Finally, we focus on the dynamics of PcG protein complex action during cell fate transitions and on the implications of histone modifications for cell lineage commitment.

[1]  Jürg Müller,et al.  Biochemical mechanisms of gene regulation by polycomb group protein complexes. , 2009, Current opinion in genetics & development.

[2]  Michael B. Stadler,et al.  Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. , 2008, Molecular cell.

[3]  O. Cuvier,et al.  Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1 , 2005, Nature.

[4]  Gangning Liang,et al.  Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line , 2008, Proceedings of the National Academy of Sciences.

[5]  C. Muchardt,et al.  The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation. , 2009, Genes & development.

[6]  R. Paro,et al.  Evolutionary Plasticity of Polycomb/Trithorax Response Elements in Drosophila Species , 2008, PLoS biology.

[7]  Daniel Chourrout,et al.  Genome Regulation by Polycomb and Trithorax Proteins , 2007, Cell.

[8]  R. Kingston,et al.  The Core of the Polycomb Repressive Complex Is Compositionally and Functionally Conserved in Flies and Humans , 2002, Molecular and Cellular Biology.

[9]  M. van Lohuizen,et al.  Stem cell regulation by polycomb repressors: postponing commitment. , 2008, Current opinion in cell biology.

[10]  Guo-Cheng Yuan,et al.  EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. , 2008, Molecular cell.

[11]  E. Lewis A gene complex controlling segmentation in Drosophila , 1978, Nature.

[12]  Juri Rappsilber,et al.  A model for transmission of the H3K27me3 epigenetic mark , 2008, Nature Cell Biology.

[13]  Jo Handelsman,et al.  EPIGENETIC REGULATION OF CELLULAR MEMORY BY THE POLYCOMB AND TRITHORAX GROUP PROTEINS , 2008 .

[14]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[15]  T. Mikkelsen,et al.  Genome-scale DNA methylation maps of pluripotent and differentiated cells , 2008, Nature.

[16]  M. Akam,et al.  The molecular basis for metameric pattern in the Drosophila embryo. , 1987, Development.

[17]  S. Tillib,et al.  The bithorax complex is regulated by trithorax earlier during Drosophila embryogenesis than is the Antennapedia complex, correlating with a bithorax-like expression pattern of distinct early trithorax transcripts. , 1994, Development.

[18]  Howard Y. Chang,et al.  Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs , 2007, Cell.

[19]  Atif Shahab,et al.  Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. , 2007, Cell stem cell.

[20]  L. Ringrose Polycomb comes of age: genome-wide profiling of target sites. , 2007, Current opinion in cell biology.

[21]  E. Heard Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. , 2005, Current opinion in genetics & development.

[22]  J. García-Verdugo,et al.  Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells , 2009, Nature.

[23]  H. Ding,et al.  Bmi-1 Regulates the Differentiation and Clonogenic Self-renewal of I-type Neuroblastoma Cells in a Concentration-dependent Manner* , 2006, Journal of Biological Chemistry.

[24]  N. Negre,et al.  From genetics to epigenetics: the tale of Polycomb group and trithorax group genes , 2006, Chromosome Research.

[25]  R. Kingston,et al.  Stabilization of Chromatin Structure by PRC1, a Polycomb Complex , 1999, Cell.

[26]  Min Gyu Lee,et al.  Demethylation of H3K27 Regulates Polycomb Recruitment and H2A Ubiquitination , 2007, Science.

[27]  A. Busturia,et al.  A silencer is required for maintenance of transcriptional repression throughout Drosophila development. , 1997, Development.

[28]  R. Young,et al.  H2AZ Is Enriched at Polycomb Complex Target Genes in ES Cells and Is Necessary for Lineage Commitment , 2008, Cell.

[29]  Dustin E. Schones,et al.  Dynamic Regulation of Nucleosome Positioning in the Human Genome , 2008, Cell.

[30]  S. Tillib,et al.  The Drosophila trithorax gene encodes a chromosomal protein and directly regulates the region-specific homeotic gene fork head. , 1994, Genes & development.

[31]  S. Orkin,et al.  PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos , 2008, Nature Genetics.

[32]  Michael R. Green,et al.  Inappropriate Gene Activation in FSHD A Repressor Complex Binds a Chromosomal Repeat Deleted in Dystrophic Muscle , 2002, Cell.

[33]  P. Adler,et al.  Drosophila genes Posterior Sex Combs and Suppressor two of zeste encode proteins with homology to the murine bmi-1 oncogene , 1991, Nature.

[34]  Sheryl T. Smith,et al.  Association of trxG and PcG proteins with the bxd maintenance element depends on transcriptional activity , 2008, Development.

[35]  Shirley Wu,et al.  Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a). , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  I. Duncan Polycomblike: a gene that appears to be required for the normal expression of the bithorax and antennapedia gene complexes of Drosophila melanogaster. , 1982, Genetics.

[37]  Simon Kasif,et al.  Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains , 2008, PLoS genetics.

[38]  G. Hannon,et al.  Ezh2 Orchestrates Gene Expression for the Stepwise Differentiation of Tissue-Specific Stem Cells , 2009, Cell.

[39]  Yi Zhang,et al.  Hierarchical recruitment of polycomb group silencing complexes. , 2004, Molecular cell.

[40]  T. Swigut,et al.  H3K27 Demethylases, at Long Last , 2007, Cell.

[41]  Michel Bellis,et al.  Chromosomal Distribution of PcG Proteins during Drosophila Development , 2006, PLoS biology.

[42]  Christoph Wülfing,et al.  Polycomb Group Protein Ezh2 Controls Actin Polymerization and Cell Signaling , 2005, Cell.

[43]  Henriette O'Geen,et al.  Suz12 binds to silenced regions of the genome in a cell-type-specific manner. , 2006, Genome research.

[44]  M. Frasch,et al.  Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2 , 1991, Nature.

[45]  A. Aszódi,et al.  H3K27me3 forms BLOCs over silent genes and intergenic regions and specifies a histone banding pattern on a mouse autosomal chromosome. , 2009, Genome research.

[46]  D. Reinberg,et al.  Role of the polycomb protein EED in the propagation of repressive histone marks , 2009, Nature.

[47]  A. Mohd-Sarip,et al.  Pleiohomeotic Can Link Polycomb to DNA and Mediate Transcriptional Repression , 2002, Molecular and Cellular Biology.

[48]  Matthew S Macauley,et al.  Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc) , 2009, Proceedings of the National Academy of Sciences.

[49]  Rolf Bodmer,et al.  MBLR, a new RING finger protein resembling mammalian Polycomb gene products, is regulated by cell cycle‐dependent phosphorylation , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[50]  Jürg Müller,et al.  Histone trimethylation and the maintenance of transcriptional ON and OFF states by trxG and PcG proteins. , 2006, Genes & development.

[51]  Malgorzata Schelder,et al.  A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. , 2006, Genes & development.

[52]  P. Pandolfi,et al.  Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. , 2002, Developmental cell.

[53]  Giacomo Cavalli,et al.  Polycomb group proteins and long-range gene regulation. , 2008, Advances in genetics.

[54]  A. Shearn,et al.  A screen for new trithorax group genes identified little imaginal discs, the Drosophila melanogaster homologue of human retinoblastoma binding protein 2. , 2000, Genetics.

[55]  K. Helin,et al.  Polycomb Complex 2 Is Required for E-cadherin Repression by the Snail1 Transcription Factor , 2008, Molecular and Cellular Biology.

[56]  G. Natoli,et al.  The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene Silencing , 2007, Cell.

[57]  Hengbin Wang,et al.  Role of hPHF1 in H3K27 Methylation and Hox Gene Silencing , 2007, Molecular and Cellular Biology.

[58]  Yi Zhang,et al.  The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. , 2004, Current opinion in genetics & development.

[59]  J. Komorowski,et al.  Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. , 2008, Molecular cell.

[60]  Hana Kim,et al.  AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2 , 2009 .

[61]  Paul Tempst,et al.  Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. , 2004, Molecular cell.

[62]  K. Helin,et al.  Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. , 2008, Genes & development.

[63]  David M. Livingston,et al.  A Complex with Chromatin Modifiers That Occupies E2F- and Myc-Responsive Genes in G0 Cells , 2002, Science.

[64]  R. Kingston,et al.  A Drosophila Polycomb group complex includes Zeste and dTAFII proteins , 2001, Nature.

[65]  Richard Bourgon,et al.  Genome-wide analysis of Polycomb targets in Drosophila melanogaster , 2006, Nature Genetics.

[66]  B. Steensel,et al.  Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster , 2006, Nature Genetics.

[67]  D. Reinberg,et al.  Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Yi Zhang,et al.  SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. , 2004, Molecular cell.

[69]  A. Iwama,et al.  Bmi1 cooperates with Dnmt1-associated protein 1 in gene silencing. , 2007, Biochemical and biophysical research communications.

[70]  M. Hild,et al.  Comparing active and repressed expression states of genes controlled by the Polycomb/Trithorax group proteins , 2007, Proceedings of the National Academy of Sciences.

[71]  Jeroen A. A. Demmers,et al.  dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group silencing. , 2008, Genes & development.

[72]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[73]  Y. Sancak,et al.  Tissue-Specific TAFs Counteract Polycomb to Turn on Terminal Differentiation , 2005, Science.

[74]  Jürg Müller,et al.  Essential Role of the Glycosyltransferase Sxc/Ogt in Polycomb Repression , 2009, Science.

[75]  M. Begemann,et al.  Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective , 2007, Stem cells.

[76]  F. P. Villena,et al.  Genome imprinting regulated by the mouse Polycomb group protein Eed , 2003, Nature Genetics.

[77]  In Hye Lee,et al.  Bmi1 regulates mitochondrial function and the DNA damage response pathway , 2009, Nature.

[78]  Haruhiko Koseki,et al.  Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells , 2007, Nature Cell Biology.

[79]  Atsushi Hijikata,et al.  Maintenance of Undifferentiated State and Self‐Renewal of Embryonic Neural Stem Cells by Polycomb Protein Ring1B , 2009, Stem cells.

[80]  Jeannie T. Lee Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome. , 2009, Genes & development.

[81]  Jeannie T. Lee,et al.  Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome , 2008, Science.

[82]  Kristian Helin,et al.  Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. , 2006, Genes & development.

[83]  Jürg Müller,et al.  General transcriptional silencing by a Polycomb response element in Drosophila , 2004, Development.

[84]  V. Pirrotta,et al.  ESC, ESCL and their roles in Polycomb Group mechanisms , 2008, Mechanisms of Development.

[85]  H. Stunnenberg,et al.  Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes , 2007, The EMBO journal.

[86]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[87]  Amos Tanay,et al.  Functional Anatomy of Polycomb and Trithorax Chromatin Landscapes in Drosophila Embryos , 2009, PLoS biology.

[88]  Antoine H. F. M. Peters,et al.  Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. , 2008, Developmental cell.

[89]  T. Jenuwein,et al.  Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. , 2007, Cancer cell.

[90]  Brigitte Wild,et al.  Histone Methyltransferase Activity of a Drosophila Polycomb Group Repressor Complex , 2002, Cell.

[91]  Gerald W. Hart,et al.  Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins , 2007, Nature.

[92]  C. Fritsch,et al.  The Drosophila pho-like gene encodes a YY1-related DNA binding protein that is redundant with pleiohomeotic in homeotic gene silencing , 2003, Development.

[93]  Yuri B Schwartz,et al.  Polycomb Complexes and the Propagation of the Methylation Mark at the Drosophila Ubx Gene* , 2006, Journal of Biological Chemistry.

[94]  J. B. Jaynes,et al.  Transcription of bxd Noncoding RNAs Promoted by Trithorax Represses Ubx in cis by Transcriptional Interference , 2006, Cell.

[95]  J. A. Wamstad,et al.  Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 Targets , 2006, Molecular and Cellular Biology.

[96]  S. Orkin,et al.  Supplemental Data EZH 1 Mediates Methylation on Histone H 3 Lysine 27 and Complements EZH 2 in Maintaining Stem Cell Identity and Executing Pluripotency , 2008 .

[97]  R. Roeder,et al.  GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis , 2009, Nature.

[98]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[99]  Yuri B Schwartz,et al.  Polycomb complexes and epigenetic states. , 2008, Current opinion in cell biology.

[100]  N. Brockdorff,et al.  A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin. , 2007, Molecular cell.

[101]  V. Pirrotta,et al.  Drosophila Enhancer of Zeste/ESC Complexes Have a Histone H3 Methyltransferase Activity that Marks Chromosomal Polycomb Sites , 2002, Cell.

[102]  G. Hart,et al.  Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. , 2007, Nature.

[103]  Kristian Helin,et al.  The Polycomb Group Protein Suz12 Is Required for Embryonic Stem Cell Differentiation , 2007, Molecular and Cellular Biology.

[104]  Mark Ptashne,et al.  On the use of the word ‘epigenetic’ , 2007, Current Biology.

[105]  P. Johnston Review of Development , 2006 .

[106]  Giacomo Cavalli,et al.  Polyhomeotic has a tumor suppressor activity mediated by repression of Notch signaling , 2009, Nature Genetics.

[107]  David Bilder,et al.  A tumor suppressive activity of Drosophila Polycomb genes mediated by JAK/STAT signaling , 2009, Nature Genetics.

[108]  Julien Gagneur,et al.  Dynamic regulation by polycomb group protein complexes controls pattern formation and the cell cycle in Drosophila. , 2008, Developmental cell.

[109]  Anke Sparmann,et al.  Polycomb silencers control cell fate, development and cancer , 2006, Nature Reviews Cancer.

[110]  M. Fraga,et al.  The Polycomb group protein EZH2 directly controls DNA methylation , 2006, Nature.

[111]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[112]  Giacomo Cavalli,et al.  The role of Polycomb Group Proteins in Cell Cycle Regulation During Development , 2006, Cell cycle.

[113]  Leonie Ringrose,et al.  Non-coding RNAs in Polycomb/Trithorax regulation , 2009, RNA biology.

[114]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[115]  D. Reinberg,et al.  Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. , 2002, Genes & development.

[116]  G. Pan,et al.  Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. , 2007, Cell stem cell.

[117]  Hana Kim,et al.  AEBP 2 as a potential targeting protein for Polycomb Repression Complex PRC 2 , 2009 .

[118]  S. Henikoff,et al.  Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks , 2008, Nature.

[119]  D. Reinberg,et al.  Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. , 2008, Molecular cell.

[120]  K. Helin,et al.  Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A‐ARF locus , 2007, The EMBO journal.

[121]  J. Robert Manak,et al.  Stability and Dynamics of Polycomb Target Sites in Drosophila Development , 2008, PLoS genetics.

[122]  Jürg Müller,et al.  Polycomb response elements and targeting of Polycomb group proteins in Drosophila. , 2006, Current opinion in genetics & development.

[123]  Terry Magnuson,et al.  Polycomb Repressive Complex 2 Is Dispensable for Maintenance of Embryonic Stem Cell Pluripotency , 2008, Stem cells.

[124]  Stephan C. Schuster,et al.  Nucleosome organization in the Drosophila genome , 2008, Nature.

[125]  D. Reinberg,et al.  Ezh2 Requires PHF1 To Efficiently Catalyze H3 Lysine 27 Trimethylation In Vivo , 2008, Molecular and Cellular Biology.

[126]  Hengbin Wang,et al.  Role of hPHF1 in H3K27 Methylation and Hox Gene Silencing , 2007, Molecular and Cellular Biology.

[127]  Kristian Helin,et al.  The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. , 2007, Genes & development.

[128]  G. Lyons,et al.  The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. , 2004, Genes & development.

[129]  R. Paro,et al.  Suppression of Polycomb group proteins by JNK signalling induces transdetermination in Drosophila imaginal discs , 2005, Nature.