Advertisement

Transcriptional Regulation in Embryonic Stem Cells

  • Jian-Chien Dominic Heng
  • Huck-Hui Ng
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 695)

Abstract

Transcriptional regulation is a pivotal process that confers cellular identity and modulates the biological activities within a cell. In embryonic stem cells (ESCs), the intricate interplay between transcription factors and their targets on the genomic template serves as building blocks for the transcriptional network that governs self-renewal and pluripotency. At the heart of this complex network is the transcription factor trio, Oct4, Sox2 and Nanog, which constitute the ESC transcriptional core. Regulatory mechanisms such as autoregulatory and feedforward loops support the ESC transcriptional framework and serve as homeostatic control for ESC maintenance. Large-scale studies such as loss of function RNAi screens and transcriptome analysis have led to the identification of more players that support pluripotency. In addition, genome-wide localization studies of transcription factors have further unraveled the interconnectivity within the ESC transcriptional circuitry. Transcription factors also work in concert with epigenetic factors and together, this crosstalk between transcriptional and epigenetic regulation maintains the homeostasis of ESC. This chapter provides an overview of the significance of transcriptional regulation in ESC and traces the recent advances made in dissecting the ESC transcriptional regulatory network.

Keywords

Embryonic Stem Cell Leukemia Inhibitory Factor Mouse Embryonic Stem Cell Inner Cell Mass Transcriptional Network 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lander ES, Linton LM, Birren B et al. Initial sequencing and analysis of the human genome. Nature 2001; 409:860–921.CrossRefPubMedGoogle Scholar
  2. 2.
    Johnson KM, Mitsouras K, Carey M. Eukaryotic transcription: the core of eukaryotic gene activation. Curr Biol 2001; 11:R510–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Levine M, Tjian R. Transcription regulation and animal diversity. Nature 2003; 424:147–51.CrossRefPubMedGoogle Scholar
  4. 4.
    Pesce M, Scholer HR. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 2001; 19:271–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Nichols J, Zevnik B, Anastassiadis K et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 1998; 95:379–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 2000; 24:372–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Niwa H, Toyooka Y, Shimosato D et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 2005; 123:917–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Avilion AA, Nicolis SK, Pevny LH et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 2003; 17:126–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Masui S, Nakatake Y, Toyooka Y et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 2007; 9:625–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Kopp JL, Ormsbee BD, Desler M et al. Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells 2008; 26:903–911.CrossRefPubMedGoogle Scholar
  11. 11.
    Rodda DJ, Chew JL, Lim LH et al. Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 2005; 280:24731–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Kuroda T, Tada M, Kubota H et al. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol 2005; 25:2475–85.CrossRefPubMedGoogle Scholar
  13. 13.
    Ambrosetti DC, Scholer HR, Dailey L et al. Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer. J Biol Chem 2000; 275:23387–97.CrossRefPubMedGoogle Scholar
  14. 14.
    Ambrosetti DC, Basilico C, Dailey L. Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol 1997; 17:6321–9.PubMedGoogle Scholar
  15. 15.
    Botquin V, Hess H, Fuhrmann G et al. New POU dimer configuration mediates antagonistic control of an osteopontin preimplantation enhancer by Oct-4 and Sox-2. Genes Dev 1998; 12:2073–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Nishimoto M, Fukushima A, Okuda A et al. The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol 1999; 19:5453–65.PubMedGoogle Scholar
  17. 17.
    Yuan H, Corbi N, Basilico C et al. Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 1995; 9:2635–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Chew JL, Loh YH, Zhang W et al. Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/ Sox2 complex in embryonic stem cells. Mol Cell Biol 2005; 25:6031–46.CrossRefPubMedGoogle Scholar
  19. 19.
    Okumura-Nakanishi S, Saito M, Niwa H et al. Oct-3/4 and Sox2 Regulate Oct-3/4 Gene in Embryonic Stem Cells. J Biol Chem 2005; 280:5307–5317.CrossRefPubMedGoogle Scholar
  20. 20.
    Remenyi A, Lins K, Nissen LJ et al. Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers. Genes Dev 2003; 17:2048–59.CrossRefPubMedGoogle Scholar
  21. 21.
    Williams DC, Jr., Cai M, Clore GM. Molecular basis for synergistic transcriptional activation by Oct1 and Sox2 revealed from the solution structure of the 42-kDa Oct1.Sox2.Hoxb1-DNA ternary transcription factor complex. J Biol Chem 2004; 279:1449–57.CrossRefPubMedGoogle Scholar
  22. 22.
    Maruyama M, Ichisaka T, Nakagawa M et al. Differential roles for Sox15 and Sox2 in transcriptional control in mouse embryonic stem cells. J Biol Chem 2005; 280:24371–24379.CrossRefPubMedGoogle Scholar
  23. 23.
    Mullin N P, Yates A, Rowe AJ et al. The pluripotency rheostat Nanog functions as a dimer. Biochem J 2008; 227–231.Google Scholar
  24. 24.
    Wang W, Lin C, Lu D et al. Chromosomal transposition of PiggyBac in mouse embryonic stem cells. Proc Natl Acad Sci USA 2008; 105:9290–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Chambers I, Colby D, Robertson M et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003; 113:643–55.CrossRefPubMedGoogle Scholar
  26. 26.
    Mitsui K, Tokuzawa Y, Itoh H et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 2003; 113:631–42.CrossRefPubMedGoogle Scholar
  27. 27.
    Ivanova N, Dobrin R, Lu R et al. Dissecting self-renewal in stem cells with RNA interference. Nature 2006; 442:533–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Loh YH, Wu Q, Chew JL et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 2006; 38:431–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Chambers I, Silva J, Colby D et al. Nanog safeguards pluripotency and mediates germline development. Nature 2007; 450:1230–4.CrossRefPubMedGoogle Scholar
  30. 30.
    Niwa H, Ogawa K, Shimosato D et al. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature 2009; 460:118–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Kalmar T, Lim C, Hayward P et al. Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 2009; 7:e1000149.CrossRefPubMedGoogle Scholar
  32. 32.
    Carter MG, Stagg CA, Falco G et al. An in situ hybridization-based screen for heterogeneously expressed genes in mouse ES cells. Gene Expr Patterns 2008; 8:181–98.CrossRefPubMedGoogle Scholar
  33. 33.
    Silva J, Nichols J, Theunissen TW et al. Nanog is the gateway to the pluripotent ground state. Cell 2009; 138:722–37.CrossRefPubMedGoogle Scholar
  34. 34.
    Jiang J, Chan YS, Loh YH et al. A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 2008; 10:353–60.CrossRefPubMedGoogle Scholar
  35. 35.
    Hall J, Guo G, Wray J et al. Oct4 and LIF/Stat3 additively induce Kruppel factors to sustain embryonic stem cell self-renewal. Cell Stem Cell 2009; 5:597–609.CrossRefPubMedGoogle Scholar
  36. 36.
    Ema M, Mori D, Niwa H et al. Kruppel-like factor 5 is essential for blastocyst development and the normal self-renewal of mouse ESCs. Cell Stem Cell 2008; 3:555–67.CrossRefPubMedGoogle Scholar
  37. 37.
    Dejosez M, Krumenacker JS, Zitur LJ et al. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 2008; 133:1162–74.CrossRefPubMedGoogle Scholar
  38. 38.
    Hu G, Kim J, Xu Q et al. A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev 2009; 23:837–48.CrossRefPubMedGoogle Scholar
  39. 39.
    Ding L, Paszkowski-Rogacz M, Nitzsche A et al. A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell 2009; 4:403–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Gaspar-Maia A, Alajem A, Polesso F et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 2009; 460:863–8.PubMedGoogle Scholar
  41. 41.
    Wang J, Rao S, Chu J et al. A protein interaction network for pluripotency of embryonic stem cells. Nature 2006; 444:364–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Wu Q, Chen X, Zhang J et al. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem 2006; 281:24090–4.CrossRefPubMedGoogle Scholar
  43. 43.
    Suzuki A, Raya A, Kawakami Y et al. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proc Natl Acad Sci USA 2006; 103:10294–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Torres J, Watt FM. Nanog maintains pluripotency of mouse embryonic stem cells by inhibiting NFkappaB and cooperating with Stat3. Nat Cell Biol 2008; 10:194–201.CrossRefPubMedGoogle Scholar
  45. 45.
    Araki R, Fukumura R, Sasaki N et al. More than 40,000 transcripts, including novel and noncoding transcripts, in mouse embryonic stem cells. Stem Cells 2006; 24:2522–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Sharov AA, Piao Y, Matoba R et al. Transcriptome analysis of mouse stem cells and early embryos. PLoS Biol 2003; 1:E74.CrossRefPubMedGoogle Scholar
  47. 47.
    Nagalakshmi U, Wang Z, Waern K et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 2008; 320:1344–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Wilhelm BT, Marguerat S, Watt S et al. Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution. Nature 2008; 453:1239–43.CrossRefPubMedGoogle Scholar
  49. 49.
    Ozsolak F, Platt AR, Jones DR et al. Direct RNA sequencing. Nature 2009; 461:814–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Boyer LA, Lee TI, Cole MF et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005; 122:947–56.CrossRefPubMedGoogle Scholar
  51. 51.
    Kim J, Chu J, Shen X et al. An extended transcriptional network for pluripotency of embryonic stem cells. Cell 2008; 132:1049–1061.CrossRefPubMedGoogle Scholar
  52. 52.
    Chen X, Xu H, Yuan P et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008; 133:1106–17.CrossRefPubMedGoogle Scholar
  53. 53.
    Johnson DS, Mortazavi A, Myers RM et al. Genome-wide mapping of in vivo protein-DNA interactions. Science 2007; 316:1497–502.CrossRefPubMedGoogle Scholar
  54. 54.
    Jothi R, Cuddapah S, Barski A et al. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 2008; 36:5221–31.CrossRefPubMedGoogle Scholar
  55. 55.
    Zhou Q, Chipperfield H, Melton DA et al. A gene regulatory network in mouse embryonic stem cells. Proc Natl Acad Sci USA 2007; 104:16438–43.CrossRefPubMedGoogle Scholar
  56. 56.
    Walker E, Ohishi M, Davey RE et al. Prediction and testing of novel transcriptional networks regulating embryonic stem cell self-renewal and commitment. Cell Stem Cell 2007; 1:71–86.CrossRefPubMedGoogle Scholar
  57. 57.
    Matoba R, Niwa H, Masui S et al. Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling. PLoS ONE 2006; 1:e26.CrossRefPubMedGoogle Scholar
  58. 58.
    Thanos D, Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell 1995; 83:1091–100.CrossRefPubMedGoogle Scholar
  59. 57.
    Du W, Thanos D, Maniatis T. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell 1993; 74:887–98.CrossRefPubMedGoogle Scholar
  60. 60.
    Faiola F, Liu X, Lo S et al. Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription. Mol Cell Biol 2005; 25:10220–34.CrossRefPubMedGoogle Scholar
  61. 61.
    Ying QL, Wray J, Nichols J et al. The ground state of embryonic stem cell self-renewal. Nature 2008; 453:519–23.CrossRefPubMedGoogle Scholar
  62. 62.
    Brons IG, Smithers LE, Trotter MW et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 2007; 448:191–5.CrossRefPubMedGoogle Scholar
  63. 63.
    Tesar PJ, Chenoweth JG, Brook FA et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 2007; 448:196–9.CrossRefPubMedGoogle Scholar
  64. 64.
    Sato N, Meijer L, Skaltsounis L et al. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004; 10:55–63.CrossRefPubMedGoogle Scholar
  65. 65.
    Cole MF, Johnstone SE, Newman JJ et al. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 2008; 22:746–55.CrossRefPubMedGoogle Scholar
  66. 66.
    Pereira L, Yi F, Merrill BJ. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol Cell Biol 2006; 26:7479–91.CrossRefPubMedGoogle Scholar
  67. 67.
    Tam WL, Lim CY, Han J et al. T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways. Stem Cells 2008; 26:2019–31.CrossRefPubMedGoogle Scholar
  68. 68.
    Efroni S, Duttagupta R, Cheng J et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2008; 2:437–47.CrossRefPubMedGoogle Scholar
  69. 69.
    Meshorer E, Yellajoshula D, George E et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 2006; 10:105–16.CrossRefPubMedGoogle Scholar
  70. 70.
    Cao R, Wang L, Wang H et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298:1039–43.CrossRefPubMedGoogle Scholar
  71. 71.
    Endoh M, Endo TA, Endoh T et al. Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development 2008; 135:1513–24.CrossRefPubMedGoogle Scholar
  72. 72.
    Liang J, Wan M, Zhang Y et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol 2008; 10:731–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Yeap LS, Hayashi K, Surani MA. ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Epigenetics Chromatin 2009; 2:12.CrossRefPubMedGoogle Scholar
  74. 74.
    Yuan P, Han J, Guo G et al. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev 2009; 23:2507–20.CrossRefPubMedGoogle Scholar
  75. 75.
    Bilodeau S, Kagey MH, Frampton GM et al. SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 2009; 23:2484–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Loh YH, Zhang W, Chen X et al. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 2007; 21:2545–57.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Gene Regulation LaboratoryGenome Institute of SingaporeSingapore
  2. 2.NUS Graduate School for Integrative Sciences and EngineeringSingapore

Personalised recommendations