research-article
You have full text access to this OnlineOpen article
Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective
Article first published online: 28 JUN 2007
DOI: 10.1634/stemcells.2006-0608
Copyright © 2007 AlphaMed Press
Additional Information
How to Cite
Rajasekhar, V. K. and Begemann, M. (2007), Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective. STEM CELLS, 25: 2498–2510. doi: 10.1634/stemcells.2006-0608
Publication History
- Issue published online: 2 JAN 2009
- Article first published online: 28 JUN 2007
- Manuscript Accepted: 14 JUN 2007
- Manuscript Received: 28 SEP 2006
References
- 1. The epigenotype. Endeavour 1942; 1:18–20.
- 2, , . From genetics to epigenetics: The tale of Polycomb group and trithorax group genes. Chromosome Res 2006; 14:363–375.
- 3. Inherited epigenetic variation—revisiting soft inheritance. Nat Rev Genet 2006; 7:395–401.
- 4. Polycomb, epigenomes, and control of cell identity. Cell 2003; 112:599–606.
- 5. On the use of the word ‘epigenetic.’. Curr Biol 2007; 17:R233–236.
- 6, , . The mammalian epigenome. Cell 2007; 128:669–681.
- 7
- 8
- 9, . Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33:245–254.
- 10, , . Stem cells and cancer; the polycomb connection. Cell 2004; 118:409–418.
- 11, , et al. Epigenetic reprogramming in mammals. Hum Mol Genet 2005; 14Spec No 1:R47–58.
- 12, . Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006; 6:846–856.
- 13, . Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene 2006; 25:7663–7672.
- 14, , . The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006; 7:21–33.
- 15, , . The cancer epigenome—components and functional correlates. Genes Dev 2006; 20:3215–3231.
- 16, . The epigenomics of cancer. Cell 2007; 128:683–692.
- 17, , . Genetic and epigenetic regulators of pluripotency. Cell 2007; 128:747–762.
- 18, . Epigenetic signatures of stem-cell identity. Nat Rev Genet 2007; 8:263–271.
- 19. Beyond the sequence: Cellular organization of genome function. Cell 2007; 128:787–800.
- 20, . The transcriptional regulatory code of eukaryotic cells - insights from genome-wide analysis of chromatin organization and transcription factor binding. Curr Opin Cell Biol 2006; 18:291–298.
- 21, , . Chromatin structure and epigenetics. Biochem Pharmacol 2006; 72:1563–1569.
- 22, , . Cooperation between complexes that regulate chromatin structure and transcription. Cell 2002; 108:475–487.
- 23, , . The role of chromatin during transcription. Cell 2007; 128:707–719.
- 24, , et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000; 406:593–599.
- 25, , et al. Concise review: Epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells 2007; 25:2–9.
- 26, . Genomic DNA methylation: The mark and its mediators. Trends Biochem Sci 2006; 31:89–97.
- 27, . Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 2002; 99:3740–3745.
- 28, , et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A 2000; 97:5237–5242.
- 29, . DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat Cell Biol 2004; 6:984–990.
- 30, , et al. Epigenetic decisions in mammalian germ cells. Science 2007; 316:398–399.
- 31, , et al. Diverse epigenetic profile of novel human embryonic stem cell lines. Cell Cycle 2006; 5:416–420.
- 32, , et al. DNA methylation affects nuclear organization, histone modifications, and linker histone binding but not chromatin compaction. J Cell Biol 2007; 177:401–411.
- 33, , et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998; 19:187–191.
- 34, , et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393:386–389.
- 35. Polycomb, trithorax and the decision to differentiate. Bioessays 2006; 28:330–334.
- 36, . Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet 2007; 8:9–22.
- 37, , et al. Genome regulation by polycomb and trithorax proteins. Cell 2007; 128:735–745.
- 38, . Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 2004; 38:413–443.
- 39, , et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129:823–837.
- 40, . Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 2007; 134:223–232.
- 41, , et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 2005; 120:169–181.
- 42, , et al. A high-resolution map of active promoters in the human genome. Nature 2005; 436:876–880.
- 43, , et al. The genomic landscape of histone modifications in human T cells. Proc Natl Acad Sci U S A 2006; 103:15782–15787.
- 44, . The role of polycomb group proteins in cell cycle regulation during development. Cell Cycle 2006; 5:1189–1197.
- 45, , et al. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell 2005; 121:425–436.
- 46, . Cellular senescence, epigenetic switches and c-Myc. Cell Cycle 2006; 5:2319–2323.
- 47. Delving into the diversity of facultative heterochromatin: The epigenetics of the inactive X chromosome. Curr Opin Genet Dev 2005; 15:482–489.
- 48, , et al. Genome imprinting regulated by the mouse Polycomb group protein Eed. Nat Genet 2003; 33:502–507.
- 49, , et al. Regulation of Th2 cell development by Polycomb group gene bmi-1 through the stabilization of GATA3. J Immunol 2006; 177:7656–7664.
- 50, , et al. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 2006; 203:2247–2253.
- 51, . RNA silencing and genome regulation. Trends Cell Biol 2005; 15:251–258.
- 52, , et al. RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 2006; 124:957–971.
- 53. piRNAs in the germ line. Science 2007; 316:397.
- 54, , et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol 2006; 26:2560–2569.
- 55, , . Noncoding RNAs and gene silencing. Cell 2007; 128:763–776.
- 56, . Noncoding RNAs and intranuclear positioning in monoallelic gene expression. Cell 2007; 128:777–786.
- 57, . RNA meets chromatin. Genes Dev 2005; 19:1635–1655.
- 58, , et al. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat Struct Mol Biol 2006; 13:793–797.
- 59, , . Stem cells: From epigenetics to microRNAs. Neuron 2005; 46:363–367.
- 60, , et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 2006; 125:301–313.
- 61, . Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 2006; 5:2220–2222.
- 62. A gene complex controlling segmentation in Drosophila. Nature 1978; 276:565–570.
- 63. A gene product required for correct initiation of segmental determination in Drosophila. Nature 1981; 293:36–41.
- 64, , . Division of labor in polycomb group repression. Trends Biochem Sci 2004; 29:478–485.
- 65, , et al. Chromatin challenges during DNA replication and repair. Cell 2007; 128:721–733.
- 66, , et al. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 2004; 23:4061–4071.
- 67, , et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 2001; 21:4330–4336.
- 68, , et al. The eed mutation disrupts anterior mesoderm production in mice. Development 1995; 121:273–285.
- 69, , et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat Genet 2006; 38:694–699.
- 70, , et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet 2006; 38:700–705.
- 71, . SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 2004; 15:57–67.
- 72, , . Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell 2005; 20:845–854.
- 73, , et al. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell 2004; 14:183–193.
- 74, , . Molecular control of pluripotency. Curr Opin Genet Dev 2006; 16:455–462.
- 75, , et al. Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci U S A 2003; 100:2468–2473.
- 76, , et al. Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Mol Cell Biol 2005; 25:6694–6706.
- 77, , et al. Stem cells primed for action: Polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells. Cell Cycle 2006; 5:1411–1414.
- 78, , et al. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 2006; 20:1123–1136.
- 79
- 80, , . High-resolution mapping reveals links of HP1 with active and inactive chromatin components. PLoS Genet 2007; 3:e38.
- 81, , et al. Tissue-specific TAFs counteract Polycomb to turn on terminal differentiation. Science 2005; 310:869–872.
- 82, . To SIR with Polycomb: linking silencing mechanisms. Bioessays 2005; 27:119–121.
- 83, . Epigenetics and cancer. Genes Dev 2004; 18:2315–2335.
- 84, . Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol 2004; 16:239–246.
- 85, , et al. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci U S A 2005; 102:1859–1864.
- 86, , et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419:624–629.
- 87, , . Role of polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol 2005; 24:117–125.
- 88. Chromatin modifications and their function. Cell 2007; 128:693–705.
- 89, . The polycomb group protein complex of Drosophila melanogaster has different compositions at different target genes. Mol Cell Biol 1997; 17:6773–6783.
- 90, . Lysine methylation and ‘signaling memory’. Curr Opin Immunol 2006; 18:152–157.
- 91, , et al. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J Cell Sci 1999; 112:4627–4639.
- 92, , et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439:871–874.
- 93, . Developmental biology: Two paths to silence merge. Nature 2006; 439:794–795.
- 94, , et al. Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1. Mol Cell Biol 2005; 25:11047–11058.
- 95, , et al. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 2007; 445:214–218.
- 96, . Molecular insights into the function, fate, and prospects of stem cells. Stem Cells 2005; 23:1212–1220.Direct Link:
- 97. Stem cells, ageing and the quest for immortality. Nature 2006; 441:1080–1086.
- 98, , . Pluripotent stem cells from germ cells. Methods Enzymol 2006; 419:400–426.
- 99, , et al. Epigenetic regulation of hematopoietic stem cell self-renewal by polycomb group genes. Int J Hematol 2005; 81:294–300.
- 100, , et al. Developmental regulation of Suz 12 localization. Chromosoma 2005; 114:183–192.
- 101, , et al. The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol Cell Biol 2007; 27:3769–3779.
- 102, , et al. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 2003; 130:4235–4248.
- 103, . Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol 2006; 7:540–546.
- 104, , et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006; 441:349–353.
- 105, , et al. Chromatin signatures of pluripotent cell lines. Nat Cell Biol 2006; 8:532–538.
- 106. Toti-/pluripotential stem cells and epigenetic modifications. Neurodegener Dis 2006; 3:32–37.
- 107, , et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005; 122:947–956.
- 108, , et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 2006; 38:431–440.
- 109, , et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res 2006; 16:890–900.
- 110. Epigenetic control of hematopoietic stem cell aging, the case of Ezh2. Ann N Y Acad Sci 2007; [Epub ahead of print].
- 111, . Fibroblast growth factors as regulators of stem cell self-renewal and aging. Mech Ageing Dev 2007; 128:17–24.
- 112, . Cellular memory and hematopoietic stem cell aging. Stem Cells 2006; 24:1143–1149.
- 113, , et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 2006; 107:2170–2179.
- 114, , et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 2004; 21:843–851.
- 115, , et al. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev 1999; 13:2691–2703.
- 116, , et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004; 428:337–341.
- 117, , et al. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 2005; 19:1432–1437.
- 118, , et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003; 425:962–967.
- 119, , et al. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev 2004; 18:2627–2638.
- 120, , et al. Human embryonic stem cells have a unique epigenetic signature. Genome Res 2006; 16:1075–1083.
- 121, , et al. Global hypomethylation of the genome in XX embryonic stem cells. Nat Genet 2005; 37:1274–1279.
- 122, , et al. De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation. Development 2004; 131:975–982.
- 123, , et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 2003; 13:1192–1200.
- 124, , et al. Histone H3 lysine 9 methylation occurs rapidly at the onset of random X chromosome inactivation. Curr Biol 2002; 12:247–251.
- 125, , et al. Genomic alterations in cultured human embryonic stem cells. Nat Genet 2005; 37:1099–1103.
- 126, , et al. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J 1997; 16:6510–6520.
- 127, , et al. Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet 2001; 28:371–375.
- 128, . Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 1975; 256:640–642.
- 129, , et al. Emerging roles of Polycomb silencing in X-inactivation and stem cell maintenance. Cold Spring Harb Symp Quant Biol 2004; 69:319–326.
- 130, . The Polycomb group protein EED is dispensable for the initiation of random X-chromosome inactivation. PLoS Genet 2006; 2:e66.
- 131, , et al. The Polycomb group protein Eed protects the inactive X-chromosome from differentiation-induced reactivation. Nat Cell Biol 2006; 8:195–202.
- 132, , et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 2004; 303:666–669.
- 133, , et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 2004; 7:663–676.
- 134. Primordial germ cells in the mouse. Dev Biol 2003; 262:1–15.
- 135, , et al. Mechanism of mouse germ cell specification: A genetic program regulating epigenetic reprogramming. Cold Spring Harb Symp Quant Biol 2004; 69:1–9.
- 136, . X-chromosome activity in the germ cells of sex-reversed mouse embryos. J Reprod Fertil 1981; 63:533–537.
- 137, , et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006; 125:315–326.
- 138, , et al. Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol 2006; 4:e170.
- 139, , et al. Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature 2005; 434:533–538.
- 140, , . Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 2002; 110:339–348.
- 141, , et al. Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol Cell Biol 2004; 24:5710–5720.
- 142. Dynamic nucleosomes and gene transcription. Trends Genet 2006; 22:320–329.
- 143, , et al. Binding of trithorax and Polycomb proteins to the bithorax complex: Dynamic changes during early Drosophila embryogenesis. EMBO J 1998; 17:5141–5150.
- 144, . Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 2006; 441:1068–1074.
- 145, . The hallmarks of cancer. Cell 2000; 100:57–70.
- 146, , et al. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet 2005; 14:3129–3140.
- 147, . The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3:415–428.
- 148, , et al. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nat Genet 2006; 38:540–549.
- 149, , et al. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006; 66:8469–8476.
- 150. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 2007; 8:286–298.
- 151, , et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005; 37:391–400.
- 152, , et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005; 435:1262–1266.
- 153, , et al. Epigenetic stem cell signature in cancer. Nat Genet 2007; 39:157–158.
- 154, , . Polycomb group proteins in cell cycle progression and cancer. Cell Cycle 2004; 3:396–400.
- 155. Of mice, flies, and man: The emerging role of polycomb-group genes in human malignant lymphomas. Int J Hematol 2005; 81:281–287.
- 156, , et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 2003; 22:5323–5335.
- 157, , et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 2007; 21:1050–1063.
- 158, , . Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3:895–902.
- 159, , et al. Polycomb genes interact with the tumor suppressor genes hippo and warts in the maintenance of Drosophila sensory neuron dendrites. Genes Dev 2007; 21:956–972.
- 160, , et al. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol 2005; 70:177–185.
- 161, . Cancer: Crime and punishment. Nature 2005; 436:636–637.
- 162, , . Inflammation, a key event in cancer development. Mol Cancer Res 2006; 4:221–233.
- 163, . Inflammation and cancer. Nature 2002; 420:860–867.
- 164, . Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006; 6:107–116.
- 165, , et al. Stem cells, cancer, and cancer stem cells. Nature 2001; 414:105–111.
- 166, , . Cancer stem cells: An old idea—a paradigm shift. Cancer Res 2006; 66:1883–1890.
- 167, . Stem cells and cancer: Two faces of eve. Cell 2006; 124:1111–1115.
- 168, , et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 2007; 39:237–242.
- 169, , et al. Linking the Rb and polycomb pathways. Mol Cell 2001; 8:557–569.
- 170, . Human embryonic genes re-expressed in cancer cells. Oncogene 2001; 20:8085–8091.
- 171, , et al. Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 2005; 104:2255–2265.
- 172, , et al. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 2003; 4:361–370.
- 173, , et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 2004; 18:1875–1885.
- 174, , et al. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 2005; 121:465–477.
- 175, , . The key to development: Interpreting the histone code? Curr Opin Genet Dev 2005; 15:163–176.
- 176, , et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 2007; 39:232–236.
- 177, . Stem cell chromatin patterns: An instructive mechanism for DNA hypermethylation? Cell Cycle 2007; 6:1040–1043.
- 178. Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer 2007; 96:R26–30.
- 179, , et al. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999; 397:164–168.
- 180, , et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 2006; 443:448–452.
- 181, , et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 2005; 19:1438–1443.
- 182, , et al. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev 2007; 21:49–54.
- 183, , et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007; 21:525–530.
- 184, , et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006; 443:421–426.
- 185, , et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 2006; 443:453–457.
- 186, , et al. Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 2006; 66:4095–4099.
- 187, , et al. Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. Mol Cancer Ther 2006; 5:3096–3104.
- 188, , et al. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res 2006; 66:3541–3549.
- 189, , et al. More than structural cells, fibroblasts create and orchestrate the tumor microenvironment. Immunol Invest 2006; 35:297–325.
- 190, . Stem cells and their niches. Science 2006; 311:1880–1885.
- 191, . Context, tissue plasticity, and cancer: Are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005; 7:17–23.
- 192, . Normal stem cells and cancer stem cells: The niche matters. Cancer Res 2006; 66:4553–4557.
- 193, , et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005; 37:899–905.
- 194, , et al. Genomewide gain-of-function genetic screen identifies functionally active genes in mouse embryonic stem cells. Proc Natl Acad Sci U S A 2006; 103:6946–6951.
- 195. Chromatin and epigenetics in development: Blending cellular memory with cell fate plasticity. Development 2006; 133:2089–2094.
- 196. Chipping away at the embryonic stem cell network. Cell 2005; 122:828–830.
- 197, , . MSX1 cooperates with histone H1b for inhibition of transcription and myogenesis. Science 2004; 304:1675–1678.
- 198, , et al. PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Genes Dev 2006; 20:784–794.
- 199, , et al. E4F1: A novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev 2006; 20:2110–2120.
- 200, , et al. Architecture of a polycomb nucleoprotein complex. Mol Cell 2006; 24:91–100.
- 201. Analytical methods for cancer stem cells. In: VemuriMC, ed. Stem Cell Assays. Totowa, NJ: Humana Press, 2007;83–95.
- 202, . Gene activation and deactivation related changes in the three-dimensional structure of chromatin. Chromosoma 2005; 114:331–337.
- 203, , et al. Quantitative proteomic analysis of post-translational modifications of human histones. Mol Cell Proteomics 2006; 5:1314–1325.
- 204, , et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 2007; 39:311–318.
- 205, , . Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nat Genet 2006; 38:835–841.
- 206, . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–676.
- 207, , et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; [Epub ahead of print].
- 208, , . Generation of germline-competent induced pluripotent stem cells. Nature 2007; [Epub ahead of print].
- 209, , et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and wide spread tissue contribution. Cell Stem Cell 2007; 1:55–70.
- 210, . Cellular memory and dynamic regulation of polycomb group proteins. Curr Opin Cell Biol 2006; 18:275–283.
- 211, , et al. Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle 2006; 5:1886–1901.
- 212, , et al. Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays. Mod Pathol 2006; 19:684–694.
- 213, , et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res 2001; 61:2409–2412.
- 214, , et al. The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Genes Chromosomes Cancer 2006; 45:639–645.
- 215, , et al. Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage. Exp Hematol 2001; 29:93–103.
- 216, , et al. Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood 2001; 97:3896–3901.
- 217, , et al. Increased expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int 2005; 75:252–257.
- 218, , et al. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 2005; 16:349–353.
- 219, , et al. Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res 2005; 11:8570–8576.
- 220, , et al. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res 2006; 12:1168–1174.
- 221, , et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 2006; 24:268–273.
- 222, , et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 2003; 100:11606–11611.
- 223, , et al. Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases. Eur J Surg Oncol 2005; 31:376–380.
- 224, , et al. Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin's disease. Am J Pathol 2000; 157:709–715.
- 225, , et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer 2005; 92:1754–1758.
- 226, , et al. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br J Haematol 2001; 112:950–958.
- 227, , et al. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007; 52:455–463.
- 228, , et al. The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene 2007; 26:4590–4595.
- 229, , . Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J Biol Chem 2005; 280:22437–22444.
- 230, , et al. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci 2006; 97:484–491.
- 231, , . Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy. Mol Cancer Ther 2003; 2:113–121.
- 232, , et al. Increased expression of the EZH2 polycomb group gene in BMI-1-positive neoplastic cells during bronchial carcinogenesis. Neoplasia 2004; 6:736–743.
- 233, , et al. Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res 2006; 12:6960–6966.
- 234, , et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 2007; 104:973–978.
- 235, , et al. Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines. Am J Pathol 2004; 164:873–881.
- 236, , et al. BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. Int J Hematol 2005; 82:42–47.
- 237, , et al. Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res 2006; 66:6225–6232.
- 238, , et al. BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res 2006; 34:1745–1754.
- 239, , et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001; 84:1372–1376.
- 240, , et al. Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions. Lung Cancer 2005; 48:299–306.
- 241, , et al. Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br J Cancer 2007; 96:126–133.
- 242, , et al. Transcription factor YY1: Structure, function, and therapeutic implications in cancer biology. Oncogene 2006; 25:1125–1142.
- 243, , et al. Polycomblike-2-deficient mice exhibit normal left-right asymmetry. Dev Dyn 2007; 236:853–861.

1549-4918/asset/olbannerleft.jpg?v=1&s=699114e871887e6b838f6a1c657fe256cfe127a6)
1549-4918/asset/olbannerright.gif?v=1&s=603f8f2ab5cd9d4f783c231915608956af51aeea)
1549-4918/asset/cover.gif?v=1&s=51ac62b4272cd760b70f0cb1539035cc40743da6)