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Nuclear Reprogramming and Stem Cells pp 99–112Cite as

The Function of Nanog in Pluripotency

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Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

The transcription factors Oct4, Sox2 and Nanog form a triumvirate of regulatory proteins governing efficient maintenance of pluripotent cell identity. However, in contrast to Oct4 and Sox2, whose protein levels are relatively constant in undifferentiated mouse ES cells, Nanog levels fluctuate widely. Here, we discuss the effect of altering the dose of Nanog on self-renewal efficiency. The key role of Nanog as a self-renewal rheostat and the fact that fluctuations in Nanog level allow entry of Nanog-low cells into a differentiation-prone state are presented in relation to interactions of Nanog not only with itself but also with its partner proteins.

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References

  • Ambrosetti DC, Basilico C et al (1997) 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 17(11):6321–6329

    PubMed  CAS  Google Scholar 

  • Ambrosetti DC, Scholer HR et al (2000) 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 275(30):23387–23397

    Article  PubMed  CAS  Google Scholar 

  • Amster-Choder O, Wright A (1992) Modulation of the dimerization of a transcriptional antiterminator protein by phosphorylation. Science 257(5075):1395–1398

    Article  PubMed  CAS  Google Scholar 

  • Avilion AA, Nicolis SK et al (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17(1):126–140

    Article  PubMed  CAS  Google Scholar 

  • Banerjee-Basu S, Sink DW et al (2001) The homeodomain resource: sequences, structures, DNA binding sites and genomic information. Nucleic Acids Res 29(1):291–293

    Article  PubMed  CAS  Google Scholar 

  • Boyer LA, Lee TI et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122(6):947–956

    Article  PubMed  CAS  Google Scholar 

  • Brons IG, Smithers LE et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448(7150):191–195

    Article  PubMed  CAS  Google Scholar 

  • Chambers I, Tomlinson SR (2009) The transcriptional foundation of pluripotency. Development 136(14):2311–2322

    Article  PubMed  CAS  Google Scholar 

  • Chambers I, Colby D et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113(5):643–655

    Article  PubMed  CAS  Google Scholar 

  • Chambers I, Silva J et al (2007) Nanog safeguards pluripotency and mediates germline ­development. Nature 450(7173):1230–1234

    Article  PubMed  CAS  Google Scholar 

  • Chan RL, Gago GM et al (1998) Homeoboxes in plant development. Biochim Biophys Acta 1442(1):1–19

    Article  PubMed  CAS  Google Scholar 

  • Chaney BA, Clark-Baldwin K et al (2005) Solution structure of the K50 class homeodomain PITX2 bound to DNA and implications for mutations that cause Rieger syndrome. Biochemistry 44(20):7497–7511

    Article  PubMed  CAS  Google Scholar 

  • Chazaud C, Yamanaka Y et al (2006) Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 10(5):615–624

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Xu H et al (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133(6):1106–1117

    Article  PubMed  CAS  Google Scholar 

  • Dietrich JE, Hiiragi T (2007) Stochastic patterning in the mouse pre-implantation embryo. Development 134(23):4219–4231

    Article  PubMed  CAS  Google Scholar 

  • Hajkova P, Erhardt S et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117(1–2):15–23

    Article  PubMed  CAS  Google Scholar 

  • Hajkova P, Ancelin K et al (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452(7189):877–881

    Article  PubMed  CAS  Google Scholar 

  • Han JD, Bertin N et al (2004) Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 430(6995):88–93

    Article  PubMed  CAS  Google Scholar 

  • Hart AH, Hartley L et al (2004) Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. Dev Dyn 230(1):187–198

    Article  PubMed  CAS  Google Scholar 

  • Hatano SY, Tada M et al (2005) Pluripotential competence of cells associated with Nanog activity. Mech Dev 122(1):67–79

    Article  PubMed  CAS  Google Scholar 

  • Hochedlinger K, Plath K (2009) Epigenetic reprogramming and induced pluripotency. Development 136(4):509–523

    Article  PubMed  CAS  Google Scholar 

  • Hunter T, Karin M (1992) The regulation of transcription by phosphorylation. Cell 70(3):375–387

    Article  PubMed  CAS  Google Scholar 

  • Ivanova N, Dobrin R et al (2006) Dissecting self-renewal in stem cells with RNA interference. Nature 442(7102):533–538

    Article  PubMed  CAS  Google Scholar 

  • Jauch R, Ng CK et al (2008) Crystal structure and DNA binding of the homeodomain of the stem cell transcription factor Nanog. J Mol Biol 376(3):758–770

    Article  PubMed  CAS  Google Scholar 

  • Kasahara H, Usheva A et al (2001) Characterization of homo- and heterodimerization of cardiac Csx/Nkx2.5 homeoprotein. J Biol Chem 276(7):4570–4580

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Chu J et al (2008) An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132(6):1049–1061

    Article  PubMed  CAS  Google Scholar 

  • Lambert H, Charette SJ et al (1999) HSP27 multimerization mediated by phosphorylation-­sensitive intermolecular interactions at the amino terminus. J Biol Chem 274(14):9378–9385

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Wan M et al (2008) Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol 10(6):731–739

    Article  PubMed  CAS  Google Scholar 

  • Loh YH, Wu Q et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38(4):431–440

    Article  PubMed  CAS  Google Scholar 

  • Ma T, Wang Z et al (2009) The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency. J Biol Chem 284(24):16071–16081

    Article  PubMed  CAS  Google Scholar 

  • Mallanna SK, Ormsbee BD et al (2010) Proteomic analysis of Sox2-associated proteins during early stages of mouse embryonic stem cell differentiation identifies Sox21 as a novel regulator of stem cell fate. Stem Cells 28(10):1715–1727

    Article  PubMed  CAS  Google Scholar 

  • Masui S, Nakatake Y et al (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9(6):625–635

    Article  PubMed  CAS  Google Scholar 

  • Mitsui K, Tokuzawa Y et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113(5):631–642

    Article  PubMed  CAS  Google Scholar 

  • Mullin NP, Yates A et al (2008) The pluripotency rheostat Nanog functions as a dimer. Biochem J 411(2):227–231

    Article  PubMed  CAS  Google Scholar 

  • Navarro P, Chambers I et al (2008) Molecular coupling of Xist regulation and pluripotency. Science 321(5896):1693–1695

    Article  PubMed  CAS  Google Scholar 

  • Niakan KK, McCabe ER (2005) DAX1 origin, function, and novel role. Mol Genet Metab 86(1–2):70–83

    Article  PubMed  CAS  Google Scholar 

  • Nichols J, Zevnik B et al (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95(3):379–391

    Article  PubMed  CAS  Google Scholar 

  • Niwa H (2001) Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct 26(3):137–148

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Okita K, Nakagawa M et al (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953

    Article  PubMed  CAS  Google Scholar 

  • Palena CM, Gonzalez DH et al (1999) A monomer-dimer equilibrium modulates the interaction of the sunflower homeodomain leucine-zipper protein Hahb-4 with DNA. Biochem J 341(Pt 1):81–87

    Article  PubMed  CAS  Google Scholar 

  • Rose RB, Endrizzi JA et al (2000) High-resolution structure of the HNF-1alpha dimerization domain. Biochemistry 39(49):15062–15070

    Article  PubMed  CAS  Google Scholar 

  • Silva J, Chambers I et al (2006) Nanog promotes transfer of pluripotency after cell fusion. Nature 441(7096):997–1001

    Article  PubMed  CAS  Google Scholar 

  • Silva J, Nichols J et al (2009) Nanog is the gateway to the pluripotent ground state. Cell 138(4):722–737

    Article  PubMed  CAS  Google Scholar 

  • Sridharan R, Plath K (2008) Illuminating the black box of reprogramming. Cell Stem Cell 2(4):295–297

    Article  PubMed  CAS  Google Scholar 

  • Suzuki A, Raya A et al (2006) Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proc Natl Acad Sci USA 103(27):10294–10299

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  PubMed  CAS  Google Scholar 

  • Tesar PJ, Chenoweth JG et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448(7150):196–199

    Article  PubMed  CAS  Google Scholar 

  • Tutter AV, Kowalski MP et al (2009) A role for med12 in regulation of nanog and nanog target genes. J Biol Chem 284(6):3709–3718

    Article  PubMed  CAS  Google Scholar 

  • Vallier L, Mendjan S et al (2009) Activin/nodal signalling maintains pluripotency by controlling Nanog expression. Development 136(8):1339–1349

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Rao S et al (2006) A protein interaction network for pluripotency of embryonic stem cells. Nature 444(7117):364–368

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Levasseur DN et al (2008a) Requirement of Nanog dimerization for stem cell self-renewal and pluripotency. Proc Natl Acad Sci USA 105(17):6326–6331

    Article  PubMed  CAS  Google Scholar 

  • Wang ZX, Teh CH et al (2008b) The transcription factor Zfp281 controls embryonic stem cell pluripotency by direct activation and repression of target genes. Stem Cells 26(11):2791–2799

    Article  PubMed  CAS  Google Scholar 

  • Wilkins MR, Kummerfeld SK (2008) Sticking together? Falling apart? Exploring the dynamics of the interactome. Trends Biochem Sci 33(5):195–200

    Article  PubMed  CAS  Google Scholar 

  • Williams DC Jr, Cai M et al (2004) 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 279(2):1449–1457

    Article  PubMed  CAS  Google Scholar 

  • Wu Q, Chen X et al (2006) Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem 281(34):24090–24094

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi S, Kimura H et al (2005) Nanog expression in mouse germ cell development. Gene Expr Patterns 5(5):639–646

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi S, Kurimoto K et al (2009) Conditional knockdown of Nanog induces apoptotic cell death in mouse migrating primordial germ cells. Development 136(23):4011–4020

    Article  PubMed  CAS  Google Scholar 

  • Yamanaka S (2008) Pluripotency and nuclear reprogramming. Philos Trans R Soc Lond B Biol Sci 363(1500):2079–2087

    Article  PubMed  CAS  Google Scholar 

  • Yates A, Chambers I (2005) The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells. Biochem Soc Trans 33(Pt 6):1518–1521

    PubMed  CAS  Google Scholar 

  • Yu J, Vodyanik MA et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920

    Article  PubMed  CAS  Google Scholar 

  • Yuan H, Corbi N et al (1995) Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev 9(21):2635–2645

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Rayner S et al (2007) Successful co-immunoprecipitation of Oct4 and Nanog using cross-linking. Biochem Biophys Res Commun 361(3):611–614

    Article  PubMed  CAS  Google Scholar 

  • Zhong Z, Wen Z et al (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264(5155):95–98

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Paul Barlow for help with Fig. 9.2 and Raymond Poot, Simon Tomlinson and Paul Barlow for comments on the manuscript. Research in our lab is supported by The Wellcome Trust, the Medical Research Council of the UK and by the EU Framework 7 project EuroSyStem.

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Authors and Affiliations

  1. MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King’s Building, West Mains Road, Edinburgh, EH9 3JQ, UK

    Nicholas Mullin

  2. MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK

    Ian Chambers

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  1. Nicholas Mullin
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Correspondence to Nicholas Mullin .

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Editors and Affiliations

  1. Leeds Institute of Genetics,, Health & Therapeutics, University of Leeds, Leeds, LS2 9JT, United Kingdom

    Justin Ainscough

  2. Inst. Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Kyoto, 606-8507, Japan

    Shinya Yamanaka

  3. Inst. Frontier Medical Sciences, Kyoto University, Kawahara-cho 53, Kyoto, 606-8507, Japan

    Takashi Tada

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Mullin, N., Chambers, I. (2011). The Function of Nanog in Pluripotency. In: Ainscough, J., Yamanaka, S., Tada, T. (eds) Nuclear Reprogramming and Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-225-0_9

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