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Transcriptional Regulatory Networks in Embryonic Stem Cells

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Epigenetics and Disease

Part of the book series: Progress in Drug Research ((PDR,volume 67))

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Abstract

Transcriptional regulation is one of the most fundamental processes in biology, governing the morphology, function, and behavior of cells and thus the survival of organisms. The embryonic stem cell (ESC) provides a good model for the understanding of transcriptional regulation in vertebrate systems. Recent efforts have led to the identification of molecular events, which confer upon these cells the unique properties of pluripotency and self renewal. The core regulatory network maintaining the ESC identity involves three master regulators: Oct4, Sox2, and Nanog. Large-scale mapping studies interrogating the binding sites of these and other transcription factors showed co-occupancy of distinct sets of transcription factors. The assembly of multitranscription factor complexes could serve as a mechanism for providing specificity in regulating ESC-specific gene expression. These studies are also beginning to unravel the transcriptional regulatory networks that govern the ESC identity. Loss-of-function RNAi screens also identified novel regulatory molecules involved in the stable propagation of the ESC state. This argues for an ESC transcriptional regulation program in which interconnected transcriptional regulatory networks involving large numbers of transcription factors and epigenetic modifiers work in concert on ESC- and differentiation-specific genes to achieve cell state stability. This chapter traces the major efforts made over the past decade in dissecting the transcriptional regulatory network governing ESC identity and offers perspectives on the future directions of the field.

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References

  1. Lee TI, Rinaldi NJ, Robert F, Odom DT, Bar-Joseph Z, Gerber GK, Hannett NM, Harbison CT, Thompson CM, Simon I, Zeitlinger J, Jennings EG, Murray HL, Gordon DB, Ren B, Wyrick JJ, Tagne JB, Volkert TL, Fraenkel E, Gifford DK, Young RA (2002) Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298:799–804

    Article  PubMed  CAS  Google Scholar 

  2. Kusari AB, Molina DM, Sabbagh W Jr, Lau CS, Bardwell L (2004) A conserved protein interaction network involving the yeast MAP kinases Fus3 and Kss1. J Cell Biol 164:267–277

    Article  PubMed  CAS  Google Scholar 

  3. Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh CH, Minokawa T, Amore G, Hinman V, Arenas-Mena C, Otim O, Brown CT, Livi CB, Lee PY, Revilla R, Rust AG, Pan Z, Schilstra MJ, Clarke PJ, Arnone MI, Rowen L, Cameron RA, McClay DR, Hood L, Bolouri H (2002) A genomic regulatory network for development. Science 295:1669–1678

    Article  PubMed  CAS  Google Scholar 

  4. Schöler HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P (1990) New type of POU domain in germ line-specific protein Oct-4. Nature 344:435–439

    Article  PubMed  Google Scholar 

  5. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17:126–140

    Article  PubMed  CAS  Google Scholar 

  6. Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov A, Ko M, Niwa H (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9:625–635

    Article  PubMed  CAS  Google Scholar 

  7. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642

    Article  PubMed  CAS  Google Scholar 

  8. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655

    Article  PubMed  CAS  Google Scholar 

  9. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius KD, Chambers I, Schöler HR, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391

    Article  PubMed  CAS  Google Scholar 

  10. Niwa H, Miyazaki J, Smith A (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24:372–376

    Article  PubMed  CAS  Google Scholar 

  11. Yuan H, Corbi N, Bascilico C, Dailey L (1995) Developmental-specificity activity of the FGF-4 enhancer requires the synergistic action of Sox-2 and Oct-3. Genes Dev 9:2635–2645

    Article  PubMed  CAS  Google Scholar 

  12. Silva J, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O, Wray J, Yamanaka S, Chambers I, Smith A (2009) Nanog is the gateway to the pluripotent ground state. Cell 138:722–737

    Article  PubMed  CAS  Google Scholar 

  13. Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M, Vrana J, Jones K, Grotewold L, Smith A (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450:1230–1234

    Article  PubMed  CAS  Google Scholar 

  14. Xu RH, Sampsell-Barron TL, Gu F, Root S, Peck RM, Pan G, Yu J, Antosiewicz-Bourget J, Tian S, Stewart R, Thomson JA (2008) NANOG is a direct target of TGFb/activin-mediated SMAD signaling in human ESCs. Cell Stem Cell 3:196–206

    Article  PubMed  CAS  Google Scholar 

  15. Boyer LA, Lee TL, 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 122:947–956

    Article  PubMed  CAS  Google Scholar 

  16. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440

    Article  PubMed  CAS  Google Scholar 

  17. Feng B, Jiang JM, Kraus P, Ng JH, Dominic HJC, Chan YS, Yaw LP, Zhang WW, Loh YH, Han JY, Vega VB, Cacheux-Rataboul V, Lim B, Lufkin T, Ng HH (2009) Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 11:197–203

    Article  PubMed  CAS  Google Scholar 

  18. 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 444:364–368

    Article  PubMed  CAS  Google Scholar 

  19. Kim J, Chu JL, Shen XH, Wang JL, Orkin SH (2008) An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132:1049–1061

    Article  PubMed  CAS  Google Scholar 

  20. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117

    Article  PubMed  CAS  Google Scholar 

  21. Impey S, McCorkle SR, Cha-Molstad H, Dwyer JM, Yochum GS, Boss JM, McWeeney S, Dunn JJ, Mandel G, Goodman RH (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119:1041–1054

    PubMed  CAS  Google Scholar 

  22. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55–63

    Article  PubMed  CAS  Google Scholar 

  23. Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22:746–755

    Article  PubMed  CAS  Google Scholar 

  24. Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, Thomson JA, Zwaka TP (2008) Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133:1162–1174

    Article  PubMed  CAS  Google Scholar 

  25. Ivanova N, Dobrin R, Lu R, Kotenko I, Levorse J, DeCoste C, Schafer X, Lun Y, Lemischka IR (2006) Dissecting self-renewal in stem cells with RNA interference. Nature 442:533–538

    Article  PubMed  CAS  Google Scholar 

  26. Rao S, Orkin SH (2006) Unraveling the transcriptional network controlling ES cell pluripotency. Genome Biol 7:230

    Article  PubMed  Google Scholar 

  27. Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason MJ, Heidersbach A, Ramalho-Santos J, McManus MT, Plath K, Meshorer E, Ramalho-Santos M (2009) Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 460:863–868

    PubMed  CAS  Google Scholar 

  28. Fazzio TG, Huff JT, Panning B (2008) An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell 134:162–174

    Article  PubMed  CAS  Google Scholar 

  29. Ding L, Paszkowski-Rogacz M, Nitzsche A, Slabicki MM, Heninger AK, de Vries I, Kittler R, Junqueira M, Shevchenko A, Schulz H, Hubner N, Doss MX, Sachinidis A, Hescheler J, Iacone R, Anastassiadis K, Stewart AF, Pisabarro MT, Caldarelli A, Poser I, Theis M, Buchholz F (2009) A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell 4:403–415

    Article  PubMed  CAS  Google Scholar 

  30. Hu G, Kim J, Xu QK, Leng Y, Orkin SH, Elledge SJ (2009) A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. Genes Dev 23:837–848

    Article  PubMed  CAS  Google Scholar 

  31. Hochedlinger K, Jaenisch R (2006) Nuclear reprogramming and pluripotency. Nature 441:1061–1067

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2006) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  Google Scholar 

  33. Yamanaka S (2009) A fresh look at iPS cells. Cell 137:13–17

    Article  PubMed  CAS  Google Scholar 

  34. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  PubMed  CAS  Google Scholar 

  35. Feng B, Ng JH, Heng JC, Ng HH (2009) Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell 4:301–312

    Article  PubMed  CAS  Google Scholar 

  36. Zhao XY, Li W, Zhuo L, Liu L, Tong M, Hai T, Hao J, Guo C, Ma QW, Wang L, Zeng F, Zhou Q (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90

    Article  PubMed  CAS  Google Scholar 

  37. Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E, Horvath S, Zhou Q, Plath K (2009) Role of the murine reprogramming factors in the induction of pluripotency. Cell 136:364–377

    Article  PubMed  CAS  Google Scholar 

  38. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Aimiuwu O, Richter L, Zhang J, Khvorostov I, Ott V, Grunstein M, Lavon N, Benvenisty N, Croce CM, Clark AT, Baxter T, Pyle AD, Teitell MA, Pelegrini M, Plath K, Lowry WE (2009) Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5:111–123

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome Building, Singapore, Singapore, 138672

    Yun Shen Chan, Lin Yang & Huck-Hui Ng

  2. NUS Graduate School for Integrative Sciences and Engineering, Singapore, Singapore, 117597

    Yun Shen Chan & Huck-Hui Ng

Authors
  1. Yun Shen Chan
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  2. Lin Yang
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  3. Huck-Hui Ng
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Correspondence to Huck-Hui Ng .

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Editors and Affiliations

  1. for Biomedical Research, Part of the Novartis Research Foundation, Friedrich Miescher Institute, Maulbeerstrasse 66, Basel, 4058, Switzerland

    Susan M. Gasser

  2. BioMedical Research Co., Ltd., China Novartis Institutes for, Lane 898 Halei Road, Shanghai, 201203, China, People's Republic

    En Li

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© 2011 Springer Basel AG

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Chan, Y.S., Yang, L., Ng, HH. (2011). Transcriptional Regulatory Networks in Embryonic Stem Cells. In: Gasser, S., Li, E. (eds) Epigenetics and Disease. Progress in Drug Research, vol 67. Springer, Basel. https://doi.org/10.1007/978-3-7643-8989-5_12

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