Cell and Tissue Research

, Volume 331, Issue 1, pp 23–29

Epigenetics in embryonic stem cells: regulation of pluripotency and differentiation

Review

Abstract

Embryonic stem cells (ESC) are pluripotent cells capable of multilineage differentiation into every somatic cell type and therefore must be able to initiate transcription profiles for each of these different cells while maintaining their pluripotent state. Numerous studies have attempted to uncover the basic biology of the ESC and delineate mechanisms of pluripotency, but with limited success. However, recent studies attempting to understand the mechanisms by which gene expression is regulated in ESC have uncovered potential mechanisms that may be vitally important to their pluripotent nature. Epigenetic regulatory mechanisms include covalent modification of histone modification and DNA methylation. Studies have now shown that epigenetic mechanisms are vitally important to the pluripotent nature of ESC and that these mechanisms regulate differentiation. The epigenetic nature of the ESC has been demonstrated to be unique and its characteristics have been strongly linked to the global permissivity of gene expression and pluripotency. Unique mechanisms have also been suggested for the dynamic regulation of differentiation-associated gene expression. Additionally, epigenetic mechanisms have been indicated to play a role in the formation of the pluripotent cells of the inner cell mass in the developing blastocyst.

Keywords

Histone modifications Chromatin Pluripotency Embryonic stem cells Polycomb 

References

  1. Abeyta MJ, Clark AT, Rodriguez RT, Bodnar MS, Pera RA, Firpo MT (2004) Unique gene expression signatures of independently-derived human embryonic stem cell lines. Hum Mol Genet 13:601–608PubMedCrossRefGoogle Scholar
  2. Anguita E, Hughes J, Heyworth C, Blobel GA, Wood WG, Higgs DR (2004) Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. EMBO J 23:2841–2852PubMedCrossRefGoogle Scholar
  3. Armstrong L, Hughes O, Yung S, Hyslop L, Stewart R, Wappler I, Peters H, Walter T, Stojkovic P, Evans J, Stojkovic M, Lako M (2006a) The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Hum Mol Genet 15:1894–1913PubMedCrossRefGoogle Scholar
  4. Armstrong L, Lako M, Dean W, Stojkovic M (2006b) Epigenetic modification is central to genome reprogramming in somatic cell nuclear transfer. Stem Cells 24:805–814PubMedCrossRefGoogle Scholar
  5. Arney KL, Fisher AG (2004) Epigenetic aspects of differentiation. J Cell Sci 117:4355–4363PubMedCrossRefGoogle Scholar
  6. Azuara V, Brown KE, Williams RR, Webb N, Dillon N, Festenstein R, Buckle V, Merkenschlager M, Fisher AG (2003) Heritable gene silencing in lymphocytes delays chromatid resolution without affecting the timing of DNA replication. Nat Cell Biol 5:668–674PubMedCrossRefGoogle Scholar
  7. Azuara V, Perry P, Sauer S, Spivakov M, Jorgensen HF, John RM, Gouti M, Casanova M, Warnes G, Merkenschlager M, Fisher AG (2006) Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8:532–538PubMedCrossRefGoogle Scholar
  8. Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ 3rd, Gingeras TR, Schreiber SL, Lander ES (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120:169–181PubMedCrossRefGoogle Scholar
  9. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326PubMedCrossRefGoogle Scholar
  10. Bibikova M, Chudin E, Wu B, Zhou L, Garcia EW, Liu Y, Shin S, Plaia TW, Auerbach JM, Arking DE, Gonzalez R, Crook J, Davidson B, Schulz TC, Robins A, Khanna A, Sartipy P, Hyllner J, Vanguri P, Savant-Bhonsale S, Smith AK, Chakravarti A, Maitra A, Rao M, Barker DL, Loring JF, Fan JB (2006) Human embryonic stem cells have a unique epigenetic signature. Genome Res 16:1075–1083PubMedCrossRefGoogle Scholar
  11. Boiani M, Scholer HR (2005) Regulatory networks in embryo-derived pluripotent stem cells. Nat Rev Mol Cell Biol 6:872–884PubMedCrossRefGoogle Scholar
  12. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956PubMedCrossRefGoogle Scholar
  13. Boyer LA, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441:349–353PubMedCrossRefGoogle Scholar
  14. Cao R, Zhang Y (2004) The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev 14:155–164PubMedCrossRefGoogle Scholar
  15. Cao S, Bendall H, Hicks GG, Nashabi A, Sakano H, Shinkai Y, Gariglio M, Oltz EM, Ruley HE (2003) The high-mobility-group box protein SSRP1/T160 is essential for cell viability in day 3.5 mouse embryos. Mol Cell Biol 23:5301–5307PubMedCrossRefGoogle Scholar
  16. Chakrabarti SK, Francis J, Ziesmann SM, Garmey JC, Mirmira RG (2003) Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic beta cells. J Biol Chem 278:23617–23623PubMedCrossRefGoogle Scholar
  17. Chambers I, Smith A (2004) Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23:7150–7160PubMedCrossRefGoogle Scholar
  18. Chambeyron S, Bickmore WA (2004) Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev 18:1119–1130PubMedCrossRefGoogle Scholar
  19. Chambeyron S, Da Silva NR, Lawson KA, Bickmore WA (2005) Nuclear re-organisation of the Hoxb complex during mouse embryonic development. Development 132:2215–2223PubMedCrossRefGoogle Scholar
  20. Chazaud C, Yamanaka Y, Pawson T, Rossant J (2006) Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 10:615–624PubMedCrossRefGoogle Scholar
  21. Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR (1999) Regulation of transcription by a protein methyltransferase. Science 284:2174–2177PubMedCrossRefGoogle Scholar
  22. Eckfeldt CE, Mendenhall EM, Verfaillie CM (2005) The molecular repertoire of the “almighty” stem cell. Nat Rev Mol Cell Biol 6:726–737PubMedCrossRefGoogle Scholar
  23. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedCrossRefGoogle Scholar
  24. Evsikov AV, Solter D (2003) Comment on “‘Stemness’: transcriptional profiling of embryonic and adult stem cells” and “A stem cell molecular signature”. Science 302:393PubMedCrossRefGoogle Scholar
  25. Fortunel NO, Otu HH, Ng HH, Chen J, Mu X, Chevassut T, Li X, Joseph M, Bailey C, Hatzfeld JA, Hatzfeld A, Usta F, Vega VB, Long PM, Libermann TA, Lim B (2003) Comment on “‘Stemness’: transcriptional profiling of embryonic and adult stem cells” and “A stem cell molecular signature”. Science 302:393PubMedCrossRefGoogle Scholar
  26. Francastel C, Schubeler D, Martin DI, Groudine M (2000) Nuclear compartmentalization and gene activity. Nat Rev Mol Cell Biol 1:137–143PubMedCrossRefGoogle Scholar
  27. Fujimori T, Kurotaki Y, Miyazaki J, Nabeshima Y (2003) Analysis of cell lineage in two- and four-cell mouse embryos. Development 130:5113–5122PubMedCrossRefGoogle Scholar
  28. Gan Q, Yoshida T, McDonald OG, Owens GK (2007) Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem Cells 25:2–9PubMedCrossRefGoogle Scholar
  29. Gilbert N, Gilchrist S, Bickmore WA (2005) Chromatin organization in the mammalian nucleus. Int Rev Cytol 242:283–336PubMedCrossRefGoogle Scholar
  30. Henikoff S, Furuyama T, Ahmad K (2004) Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet 20:320–326PubMedCrossRefGoogle Scholar
  31. Houlard M, Berlivet S, Probst AV, Quivy JP, Hery P, Almouzni G, Gerard M (2006) CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells. PLoS Genet 2:e181PubMedCrossRefGoogle Scholar
  32. Isono K, Fujimura Y, Shinga J, Yamaki M, OW J, Takihara Y, Murahashi Y, Takada Y, Mizutani-Koseki Y, Koseki H (2005) Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Mol Cell Biol 25:6694–6706PubMedCrossRefGoogle Scholar
  33. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR (2002) A stem cell molecular signature. Science 298:601–604PubMedCrossRefGoogle Scholar
  34. Kaji K, Nichols J, Hendrich B (2007) Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134:1123–1132PubMedCrossRefGoogle Scholar
  35. Kanellopoulou C, Muljo SA, Kung AL, Ganesan S, Drapkin R, Jenuwein T, Livingston DM, Rajewsky K (2005) Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 19:489–501PubMedCrossRefGoogle Scholar
  36. Kim DH, Villeneuve LM, Morris KV, Rossi JJ (2006) Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat Struct Mol Biol 13:793–797PubMedCrossRefGoogle Scholar
  37. Kimura H, Tada M, Nakatsuji N, Tada T (2004) Histone code modifications on pluripotential nuclei of reprogrammed somatic cells. Mol Cell Biol 24:5710–5720PubMedCrossRefGoogle Scholar
  38. Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, Farnham PJ (2004) Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev 18:1592–1605PubMedCrossRefGoogle Scholar
  39. Klochendler-Yeivin A, Fiette L, Barra J, Muchardt C, Babinet C, Yaniv M (2000) The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep 1:500–506PubMedGoogle Scholar
  40. Kurisaki A, Hamazaki TS, Okabayashi K, Iida T, Nishine T, Chonan R, Kido H, Tsunasawa S, Nishimura O, Asashima M, Sugino H (2005) Chromatin-related proteins in pluripotent mouse embryonic stem cells are downregulated after removal of leukemia inhibitory factor. Biochem Biophys Res Commun 335:667–675PubMedCrossRefGoogle Scholar
  41. Lande-Diner L, Zhang J, Ben-Porath I, Amariglio N, Keshet I, Hecht M, Azuara V, Fisher AG, Rechavi G, Cedar H (2007) Role of DNA methylation in stable gene repression. J Biol Chem 282:12194–12200PubMedCrossRefGoogle Scholar
  42. Lee JH, Hart SR, Skalnik DG (2004) Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis 38:32–38PubMedCrossRefGoogle Scholar
  43. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, Koseki H, Fuchikami T, Abe K, Murray HL, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Sun K, Odom DT, Otte AP, Volkert TL, Bartel DP, Melton DA, Gifford DK, Jaenisch R, Young RA (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313PubMedCrossRefGoogle Scholar
  44. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (2003) Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13:1192–1200PubMedCrossRefGoogle Scholar
  45. Ma H, Baumann CT, Li H, Strahl BD, Rice R, Jelinek MA, Aswad DW, Allis CD, Hager GL, Stallcup MR (2001) Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter. Curr Biol 11:1981–1985PubMedCrossRefGoogle Scholar
  46. Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? Curr Opin Genet Dev 15:163–176PubMedCrossRefGoogle Scholar
  47. Martens JH, O’Sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005) The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J 24:800–812PubMedCrossRefGoogle Scholar
  48. Meshorer E, Misteli T (2006) Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol 7:540–546PubMedCrossRefGoogle Scholar
  49. Meshorer E, Yellajoshula D, George E, Scambler PJ, Brown DT, Misteli T (2006) Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 10:105–116PubMedCrossRefGoogle Scholar
  50. Morgan HD, Santos F, Green K, Dean W, Reik W (2005) Epigenetic reprogramming in mammals. Hum Mol Genet 14 (Spec No 1):R47–R58PubMedCrossRefGoogle Scholar
  51. O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21:4330–4336PubMedCrossRefGoogle Scholar
  52. O’Neill LP, VerMilyea MD, Turner BM (2006) Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nat Genet 38:835–841PubMedCrossRefGoogle Scholar
  53. Parada L, Misteli T (2002) Chromosome positioning in the interphase nucleus. Trends Cell Biol 12:425–432PubMedCrossRefGoogle Scholar
  54. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–4071PubMedCrossRefGoogle Scholar
  55. Piotrowska-Nitsche K, Perea-Gomez A, Haraguchi S, Zernicka-Goetz M (2005) Four-cell stage mouse blastomeres have different developmental properties. Development 132:479–490PubMedCrossRefGoogle Scholar
  56. Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298:597–600PubMedCrossRefGoogle Scholar
  57. Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425–432PubMedCrossRefGoogle Scholar
  58. Ringrose L, Paro R (2004) Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38:413–443PubMedCrossRefGoogle Scholar
  59. Schubeler D, Scalzo D, Kooperberg C, Steensel B van, Delrow J, Groudine M (2002) Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nat Genet 32:438–442PubMedCrossRefGoogle Scholar
  60. Schubeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F, Gottschling DE, O’Neill LP, Turner BM, Delrow J, Bell SP, Groudine M (2004) The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 18:1263–1271PubMedCrossRefGoogle Scholar
  61. Shiota K, Kogo Y, Ohgane J, Imamura T, Urano A, Nishino K, Tanaka S, Hattori N (2002) Epigenetic marks by DNA methylation specific to stem, germ and somatic cells in mice. Genes Cells 7:961–969PubMedCrossRefGoogle Scholar
  62. Spector DL (2003) The dynamics of chromosome organization and gene regulation. Annu Rev Biochem 72:573–608PubMedCrossRefGoogle Scholar
  63. Sperger JM, Chen X, Draper JS, Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, Thomson JA (2003) Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci USA 100:13350–13355PubMedCrossRefGoogle Scholar
  64. Sproul D, Gilbert N, Bickmore WA (2005) The role of chromatin structure in regulating the expression of clustered genes. Nat Rev Genet 6:775–781PubMedCrossRefGoogle Scholar
  65. Steensel B van (2005) Mapping of genetic and epigenetic regulatory networks using microarrays. Nat Genet 37 Suppl:S18–S24PubMedCrossRefGoogle Scholar
  66. Stewart R, Stojkovic M, Lako M (2006) Mechanisms of self-renewal in human embryonic stem cells. Eur J Cancer 42:1257–1272PubMedCrossRefGoogle Scholar
  67. Stojkovic M, Lako M, Stojkovic P, Stewart R, Przyborski S, Armstrong L, Evans J, Herbert M, Hyslop L, Ahmad S, Murdoch A, Strachan T (2004) Derivation of human embryonic stem cells from day-8 blastocysts recovered after three-step in vitro culture. Stem Cells 22:790–797PubMedCrossRefGoogle Scholar
  68. Strelchenko N, Verlinsky O, Kukharenko V, Verlinsky Y (2004) Morula-derived human embryonic stem cells. Reprod Biomed Online 9:623–629PubMedCrossRefGoogle Scholar
  69. Szutorisz H, Canzonetta C, Georgiou A, Chow CM, Tora L, Dillon N (2005) Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage. Mol Cell Biol 25:1804–1820PubMedCrossRefGoogle Scholar
  70. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  71. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedCrossRefGoogle Scholar
  72. Torres-Padilla ME, Parfitt DE, Kouzarides T, Zernicka-Goetz M (2007) Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445:214–218PubMedCrossRefGoogle Scholar
  73. Vieira KF, Levings PP, Hill MA, Crusselle VJ, Kang SH, Engel JD, Bungert J (2004) Recruitment of transcription complexes to the beta-globin gene locus in vivo and in vitro. J Biol Chem 279:50350–50357PubMedCrossRefGoogle Scholar
  74. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, Launoit Y de, Fuks F (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874PubMedCrossRefGoogle Scholar
  75. Vogel G (2003) Stem cells. “Stemness” genes still elusive. Science 302:371PubMedCrossRefGoogle Scholar
  76. Voncken JW, Roelen BA, Roefs M, Vries S de, Verhoeven E, Marino S, Deschamps J, Lohuizen M van (2003) Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci USA 100:2468–2473PubMedCrossRefGoogle Scholar
  77. Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH (2006) A protein interaction network for pluripotency of embryonic stem cells. Nature 444:364–368PubMedCrossRefGoogle Scholar
  78. Wassenegger M (2005) The role of the RNAi machinery in heterochromatin formation. Cell 122:13–16PubMedCrossRefGoogle Scholar
  79. Wiblin AE, Cui W, Clark AJ, Bickmore WA (2005) Distinctive nuclear organisation of centromeres and regions involved in pluripotency in human embryonic stem cells. J Cell Sci 118:3861–3868PubMedCrossRefGoogle Scholar
  80. Yamanaka S (2007) Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1:39–49CrossRefPubMedGoogle Scholar
  81. Zhang H, Christoforou A, Aravind L, Emmons SW, Heuvel S van den, Haber DA (2004) The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein. Mol Cell 14:841–847PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Institute of Human GeneticsNewcastle UniversityNewcastleUK

Personalised recommendations