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Epigenetic signatures of stem-cell identity

Key Points

  • Stem cells, including pluripotent embryonic stem (ES) cells and lineage-restricted adult stem cells, share a capacity to self-renew and generate differentiated progeny. Analysis of their epigenetic properties can help us to understand the molecular mechanism that underlies this important property.

  • Data from different approaches, including fluorescent recovery after photobleaching (FRAP) and replication timing analysis, have suggested that the chromatin of ES cells is generally less compact and more 'permissive' than that of normal cells.

  • Promoters of many non-transcribed developmental regulator genes share an unusual 'bivalent' chromatin pattern in ES cells, whereby histone modifications that are normally associated with gene transcription (acetylation at lysine 9 and trimethylation at lysine 4 of histone H3) co-exist with trimethylation at lysine 27 of histone H3, which is usually found at repressed loci.

  • These bivalent patterns are thought to keep non-transcribed genes in a 'poised' conformation, ready for expression in response to developmental cues.

  • Trimethylation of histone H3 lysine 27 is created by Polycomb repressive complex 2 (PRC2), which in turn provides a binding site for PRC1. Consistently, ES cells that are mutant for Polycomb components show derepression of several tissue-specific genes that carry bivalent chromatin marks in wild-type cells.

  • Polycomb complexes are ubiquitously expressed, whereas bivalent chromatin is unusual and is not thought to be commonly found in differentiated cells.

  • Genome-wide studies indicate that Polycomb target genes in ES cells are often co-occupied by a 'triad' of pluripotency-associated transcription factors: OCT4, SOX2 and NANOG. This suggests that these factors might have a role in recruiting Polycomb complexes to target promoters, possibly along with chromatin modifiers with an opposing function (such as histone acetyltransferases). However, many Polycomb targets in ES cells do not bind the regulatory 'triad', indicating that our knowledge of these events remains preliminary.

  • Polycomb complexes are also important for the maintenance of adult stem-cell populations. Whether they create bivalent chromatin in this context remains to be found.

Abstract

Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells, recent studies have indicated the importance of unique epigenetic profiles that keep key developmental genes 'poised' in a repressed but activatable state. Determining how these epigenetic features relate to the transcriptional signatures of ES cells, and whether they are also important in other types of stem cell, is a key challenge for the future.

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Figure 1: Bivalent chromatin profiles in ES cells.
Figure 2: Polycomb repressive complexes.
Figure 3: Integrating chromatin and transcriptional information.

References

  1. Chambers, I. & Smith, A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23, 7150–7160 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Keller, G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 19, 1129–1155 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Smith, A. G. Embryo-derived stem cells: of mice and men. Annu. Rev. Cell Dev. Biol. 17, 435–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Lovell-Badge, R. The future for stem cell research. Nature 414, 88–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Pessina, A. & Gribaldo, L. The key role of adult stem cells: therapeutic perspectives. Curr. Med. Res. Opin. 22, 2287–2300 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Johnson, B. V., Rathjen, J. & Rathjen, P. D. Transcriptional control of pluripotency: decisions in early development. Curr. Opin. Genet. Dev. 16, 447–454 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Noggle, S. A., James, D. & Brivanlou, A. H. A molecular basis for human embryonic stem cell pluripotency. Stem Cell Rev. 1, 111–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Chambers, I. The molecular basis of pluripotency in mouse embryonic stem cells. Cloning Stem Cells 6, 386–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).

    Article  CAS  PubMed  Google Scholar 

  10. Shamblott, M. J. et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc. Natl Acad. Sci. USA 95, 13726–13731 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McLaren, A. & Durcova-Hills, G. Germ cells and pluripotent stem cells in the mouse. Reprod. Fertil. Dev. 13, 661–664 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Kubota, H. & Brinster, R. L. Technology insight: in vitro culture of spermatogonial stem cells and their potential therapeutic uses. Nature Clin. Pract. Endocrinol. Metab. 2, 99–108 (2006).

    Article  CAS  Google Scholar 

  13. Nagano, M. et al. Transgenic mice produced by retroviral transduction of male germ-line stem cells. Proc. Natl Acad. Sci. USA 98, 13090–13095 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tada, M., Takahama, Y., Abe, K., Nakatsuji, N. & Tada, T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 11, 1553–1558 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Tada, M., Tada, T., Lefebvre, L., Barton, S. C. & Surani, M. A. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J. 16, 6510–6520 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. 'Stemness': transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Conti, L., Reitano, E. & Cattaneo, E. Neural stem cell systems: diversities and properties after transplantation in animal models of diseases. Brain Pathol. 16, 143–154 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fortunel, N. O. et al. Comment on 'Stemness': transcriptional profiling of embryonic and adult stem cells' and 'A stem cell molecular signature'. Science 302, 393 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Sato, N. et al. Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev. Biol. 260, 404–413 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Sperger, J. M. et al. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc. Natl Acad. Sci. USA 100, 13350–13355 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bhattacharya, B. et al. Gene expression in human embryonic stem cell lines: unique molecular signature. Blood 103, 2956–2964 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Ginis, I. et al. Differences between human and mouse embryonic stem cells. Dev. Biol. 269, 360–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Evsikov, A. V. & Solter, D. Comment on 'Stemness': transcriptional profiling of embryonic and adult stem cells' and 'A stem cell molecular signature'. Science 302, 393 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Ivanova, N. B. et al. Response to Comments on 'Stemness': transcriptional profiling of embryonic and adult stem cells' and 'A stem cell molecular signature'. Science 302, 393 (2002).

    Article  Google Scholar 

  27. Mikkers, H. & Frisen, J. Deconstructing stemness. EMBO J. 24, 2715–2719 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pritsker, M., Doniger, T. T., Kramer, L. C., Westcot, S. E. & Lemischka, I. R. Diversification of stem cell molecular repertoire by alternative splicing. Proc. Natl Acad. Sci. USA 102, 14290–14295 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Bernstein, E. & Allis, C. D. RNA meets chromatin. Genes Dev. 19, 1635–1655 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Saha, A., Wittmeyer, J. & Cairns, B. R. Chromatin remodelling: the industrial revolution of DNA around histones. Nature Rev. Mol. Cell Biol. 7, 437–447 (2006).

    Article  CAS  Google Scholar 

  33. Mostoslavsky, R., Alt, F. W. & Bassing, C. H. Chromatin dynamics and locus accessibility in the immune system. Nature Immunol. 4, 603–606 (2003).

    Article  CAS  Google Scholar 

  34. Donaldson, A. D. Shaping time: chromatin structure and the DNA replication programme. Trends Genet. 21, 444–449 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Williams, R. R. & Fisher, A. G. Chromosomes, positions please! Nature Cell Biol. 5, 388–390 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33, S245–S254 (2003).

    Article  CAS  Google Scholar 

  37. Henikoff, S., Furuyama, T. & Ahmad, K. Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet. 20, 320–326 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Nakatani, Y., Tagami, H. & Shestakova, E. How is epigenetic information on chromatin inherited after DNA replication? Ernst Schering Res. Found. Workshop 57, 89–96 (2006).

    Article  CAS  Google Scholar 

  39. Richards, E. J. Inherited epigenetic variation — revisiting soft inheritance. Nature Rev. Genet. 7, 395–401 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Smale, S. T. The establishment and maintenance of lymphocyte identity through gene silencing. Nature Immunol. 4, 607–615 (2003).

    Article  CAS  Google Scholar 

  41. Lyko, F., Beisel, C., Marhold, J. & Paro, R. Epigenetic regulation in Drosophila. Curr. Top. Microbiol. Immunol. 310, 23–44 (2006).

    CAS  PubMed  Google Scholar 

  42. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Arney, K. L. & Fisher, A. G. Epigenetic aspects of differentiation. J. Cell Sci. 117, 4355–4363 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Wiblin, A. E., Cui, W., Clark, A. J. & Bickmore, W. A. Distinctive nuclear organisation of centromeres and regions involved in pluripotency in human embryonic stem cells. J. Cell Sci. 118, 3861–3868 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Williams, R. R. et al. Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J. Cell Sci. 119, 132–140 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006). This study uses FRAP to analyse the mobility of chromatin proteins in ES cells versus differentiated cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Keohane, A. M., O'Neill, L. P., Belyaev, N. D., Lavender, J. S. & Turner, B. M. X-inactivation and histone H4 acetylation in embryonic stem cells. Dev. Biol. 180, 618–630 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Brown, K. E., Baxter, J., Graf, D., Merkenschlager, M. & Fisher, A. G. Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol. Cell 3, 207–217 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Brown, K. E. et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91, 845–854 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Su, R. C. et al. Dynamic assembly of silent chromatin during thymocyte maturation. Nature Genet. 36, 502–506 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Phair, R. D., Gorski, S. A. & Misteli, T. Measurement of dynamic protein binding to chromatin in vivo, using photobleaching microscopy. Methods Enzymol. 375, 393–414 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Brown, D. T. Histone H1 and the dynamic regulation of chromatin function. Biochem. Cell Biol. 81, 221–227 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Phair, R. D. et al. Global nature of dynamic protein–chromatin interactions in vivo: three-dimensional genome scanning and dynamic interaction networks of chromatin proteins. Mol. Cell. Biol. 24, 6393–6402 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Perry, P. et al. A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction. Cell Cycle 3, 1645–1650 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Hiratani, I., Leskovar, A. & Gilbert, D. M. Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores. Proc. Natl Acad. Sci. USA 101, 16861–16866 (2004). References 54 and 55 demonstrate that developmental genes alter their replication timing upon ES differentiation into neural progenitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Schubeler, D. et al. Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nature Genet. 32, 438–442 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Azuara, V. et al. Heritable gene silencing in lymphocytes delays chromatid resolution without affecting the timing of DNA replication. Nature Cell Biol. 5, 668–674 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Lin, C. M., Fu, H., Martinovsky, M., Bouhassira, E. & Aladjem, M. I. Dynamic alterations of replication timing in mammalian cells. Curr. Biol. 13, 1019–1028 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Simon, I. et al. Developmental regulation of DNA replication timing at the human β-globin locus. EMBO J. 20, 6150–6157 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vogelauer, M., Rubbi, L., Lucas, I., Brewer, B. J. & Grunstein, M. Histone acetylation regulates the time of replication origin firing. Mol. Cell 10, 1223–1233 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Aparicio, J. G., Viggiani, C. J., Gibson, D. G. & Aparicio, O. M. The Rpd3–Sin3 histone deacetylase regulates replication timing and enables intra-S origin control in Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 4769–4780 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nature Cell Biol. 8, 532–538 (2006). This study shows that in mouse ES cells, but not in differentiated cells, many non-transcribed developmental genes replicate early in S phase and have bivalent chromatin profiles.

    Article  CAS  PubMed  Google Scholar 

  63. Chaumeil, J., Okamoto, I., Guggiari, M. & Heard, E. Integrated kinetics of X chromosome inactivation in differentiating embryonic stem cells. Cytogenet. Genome Res. 99, 75–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006). This study identifies bivalent chromatin profiles in mouse ES cells using high-resolution ChIP-on-chip analysis.

    Article  CAS  PubMed  Google Scholar 

  65. Chambeyron, S., Da Silva, N. R., Lawson, K. A. & Bickmore, W. A. Nuclear re-organisation of the HOXB complex during mouse embryonic development. Development 132, 2215–2223 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Szutorisz, H. et al. Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage. Mol. Cell. Biol. 25, 1804–1820 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123–1136 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006). References 67 and 69 show that PcG complexes occupy promoters of repressed developmental genes in human and mouse ES cells.

    Article  CAS  PubMed  Google Scholar 

  70. Schwartz, Y. B. et al. Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nature Genet. 38, 700–705 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Negre, N. et al. Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol. 4, e170 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tolhuis, B. et al. Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nature Genet. 38, 694–699 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Jorgensen, H. F. et al. Stem cells primed for action: polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells. Cell Cycle 5, 1411–1414 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Pera, M. F. & Trounson, A. O. Human embryonic stem cells: prospects for development. Development 131, 5515–5525 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Schwartz, Y. B. & Pirrotta, V. Polycomb silencing mechanisms and the management of genomic programmes. Nature Rev. Genet. 8, 9–22 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Cao, R., Tsukada, Y. & Zhang, Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol. Cell 20, 845–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell 7, 663–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Schoeftner, S. et al. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J. 25, 3110–3122 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Min, J., Zhang, Y. & Xu, R. M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dellino, G. I. et al. Polycomb silencing blocks transcription initiation. Mol. Cell 13, 887–893 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, L. et al. Hierarchical recruitment of polycomb group silencing complexes. Mol. Cell 14, 637–646 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Mohd-Sarip, A. et al. Architecture of a Polycomb nucleoprotein complex. Mol. Cell 24, 91–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Zhang, H. et al. The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein. Mol. Cell 14, 841–847 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Kim, D. H., Villeneuve, L. M., Morris, K. V. & Rossi, J. J. Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nature Struct. Mol. Biol. 13, 793–797 (2006).

    Article  CAS  Google Scholar 

  86. Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871–874 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nature Genet. 39, 157–158 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Ohm, J. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genet. 39, 237–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nature Genet. 39, 232–236 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Boyer, L. A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Loh, Y. H. et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genet. 38, 431–440 (2006). References 90 and 91 show that key regulator genes Oct4 and Nanog bind activated as well as repressed developmental targets in human and mouse ES cells.

    Article  CAS  PubMed  Google Scholar 

  92. Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Pritsker, M., Ford, N. R., Jenq, H. T. & Lemischka, I. R. Genomewide gain-of-function genetic screen identifies functionally active genes in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 6946–6951 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gong, Y. et al. NSPc1 is a cell growth regulator that acts as a transcriptional repressor of p21Waf1/Cip1 via the RARE element. Nucleic Acids Res. 34, 6158–6169 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ivanova, N. et al. Dissecting self-renewal in stem cells with RNA interference. Nature 442, 533–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Parrish, J. R., Gulyas, K. D. & Finley, R. L. Jr . Yeast two-hybrid contributions to interactome mapping. Curr. Opin. Biotechnol. 17, 387–393 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, J. et al. A protein interaction network for pluripotency of embryonic stem cells. Nature 444, 364–368 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. O'Neill, L. P., VerMilyea, M. D. & Turner, B. M. Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nature Genet. 38, 835–841 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Dzierzak, E. The emergence of definitive hematopoietic stem cells in the mammal. Curr. Opin. Hematol. 12, 197–202 (2005).

    Article  PubMed  Google Scholar 

  101. Park, I. K. et al. BMI-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Molofsky, A. V., He, S., Bydon, M., Morrison, S. J. & Pardal, R. 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. 19, 1432–1437 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chagraoui, J. et al. E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 20, 2110–2120 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fischle, W., Wang, Y. & Allis, C. D. Histone and chromatin cross-talk. Curr. Opin. Cell Biol. 15, 172–183 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Li, E. Chromatin modification and epigenetic reprogramming in mammalian development. Nature Rev. Genet. 3, 662–673 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Lyko, F. DNA methylation learns to fly. Trends Genet. 17, 169–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Richards, E. J. & Elgin, S. C. Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell 108, 489–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Zhang, J., Xu, F., Hashimshony, T., Keshet, I. & Cedar, H. Establishment of transcriptional competence in early and late S phase. Nature 420, 198–202 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. McNairn, A. J. & Gilbert, D. M. Epigenomic replication: linking epigenetics to DNA replication. BioEssays 25, 647–656 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Orlando, V. Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem. Sci. 25, 99–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Buck, M. J. & Lieb, J. D. ChIP-chip: considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments. Genomics 83, 349–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Negre, N., Lavrov, S., Hennetin, J., Bellis, M. & Cavalli, G. Mapping the distribution of chromatin proteins by ChIP on chip. Methods Enzymol. 410, 316–341 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Wei, C. L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Gilbert, N. et al. DNA methylation affects nuclear organisation, histone modifications and linker histone binding but not chromatin compaction. J. Cell Biol. (in the press).

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Acknowledgements

M.S. and A.G.F. thank the Medical Research Council UK for continued support.

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Correspondence to Amanda G. Fisher.

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FURTHER INFORMATION

Epigenome Network of Excellence

MRC Lymphocyte Development Group

Glossary

Pluripotent

Describes cells that can, in theory, differentiate into every cell type of the adult organism.

Lineage restriction

The narrowing down of a range of differentiation pathways that a cell is able to follow.

Polycomb group proteins

A group of transcriptional repressors that are required to maintain the inactive state of genes during development. Polycomb proteins are known to modify the chromatin structure around their binding sites, which include the promoters of many developmental regulator genes.

Inner cell mass

A small clump of apparently undifferentiated cells in the blastocyst, which gives rise to the entire fetus and some of its extraembryonic membranes.

Blastocyst

An early stage of mammalian embryonic development at which the first cell lineages become established.

Primordial germ layer

An embryonic layer that will give rise to gametes in the adult organism.

DNA methylation

An epigenetically propagated covalent modification of DNA that, in mammals, occurs at cytosine deoxynucleotides. DNA methylation is thought to inhibit transcription, both by preventing transcription-factor binding to DNA and through interactions with methyl-CpG-binding proteins that recruit histone-modifying and chromatin-remodelling factors.

Small interfering RNAs

(siRNAs). Small antisense RNAs (20–25 nucleotides long) that are generated from specific dsRNAs. siRNAs trigger RNAi pathways, which negatively regulate gene expression by post-transcriptional mechanisms.

Constitutive heterochromatin

Areas of inactive chromatin that remain condensed in all tissue types. It is usually found at chromosomal regions that contain a high density of repetitive DNA elements, such as centromeres and telomeres.

Fluorescent recovery after photobleaching

A microscopy-based technique that is used to measure the movement (for example, diffusion rates) of fluorescently tagged molecules (usually proteins) over time in vivo. Specific regions in a cell are irreversibly photobleached using a laser. Over time, fluorescence is usually restored as unbleached molecules diffuse into the bleached area. The recovery time can be used as a measure of protein mobility.

Embryonic carcinoma cells

Cell lines that are derived from tumours that arise from transplantation of early-stage embryos to immunologically compatible animals. These cells can differentiate into many tissue types, and studies using them have pioneered stem-cell research. However, embryonic carcinoma cells have a significantly more restricted lineage potential than ES cells and show a high degree of variation depending on a cell line.

Carrier ChIP

A chromatin immunoprecipitation technique that uses carrier DNA to allow small amounts of starting material to be analysed.

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Spivakov, M., Fisher, A. Epigenetic signatures of stem-cell identity. Nat Rev Genet 8, 263–271 (2007). https://doi.org/10.1038/nrg2046

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