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Gene Review

Nanog  -  Nanog homeobox

Mus musculus

Synonyms: 2410002E02Rik, ENK, ES cell-associated protein 4, Early embryo specific expression NK-type homeobox protein, Ecat4, ...
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Disease relevance of Nanog


High impact information on Nanog

  • We identified 1,083 and 3,006 high-confidence binding sites for Oct4 and Nanog, respectively [2].
  • The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells [2].
  • Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog [3].
  • Extracellular signals and second messengers modulate cell-autonomous regulators such as OCT4, SOX2 and Nanog in a combinatorial complexity [4].
  • p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression [5].

Biological context of Nanog

  • The emerging picture is one in which Oct4 and Nanog control a cascade of pathways that are intricately connected to govern pluripotency, self-renewal, genome surveillance and cell fate determination [2].
  • Both the Oct4 and Nanog genes are direct targets of GCNF repression during ES cell differentiation and early mouse embryonic development [6].
  • Elevated level of Nanog can maintain the mouse ES cell self-renewal independent of LIF and enable human ES cell growth without feeder cells [7].
  • We confirm this prediction by overexpressing the H3-specific arginine methyltransferase CARM1 in individual blastomeres and show that this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2 [8].
  • Several extrinsic signals such as LIF, BMP and Wnt can support the self-renewal and pluripotency of embryonic stem (ES) cells through regulating the "pluripotent genes." A unique homeobox transcription factor, Nanog, is one of the key downstream effectors of these signals [7].

Anatomical context of Nanog

  • Thus, Cdx2 is essential for segregation of the ICM and TE lineages at the blastocyst stage by ensuring repression of Oct4 and Nanog in the TE [9].
  • Nanog expression in mouse germ cell development [10].
  • Aggregation of embryonic stem cells induces Nanog repression and primitive endoderm differentiation [11].
  • Furthermore, reactivation of the somatic cell-derived Nanog was tightly linked with nuclear reprogramming induced by cell hybridization with ES cells and by nuclear transplantation into enucleated oocytes [12].
  • Exogenous expression of Oct-3/4 or the dominant-negative mutant of STAT3 (STAT3F) by conventional Ad vectors containing the EF-1alpha promoter promoted the differentiation of mES cells into the cells of three germ layers, and STAT3F-mediated differentiation was rescued by the coexpression of Nanog [13].

Associations of Nanog with chemical compounds

  • By employing multiparameter sorting, we identified in murine bone marrow (BM) a homogenous population of rare ( approximately 0.02% of BMMNC) Sca-1(+)lin(-)CD45(-) cells that express by RQ-PCR and immunohistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1 [14].
  • Pharmacological blockade of mGlu5 receptors with 2-methyl-6-(phenylethynyl)pyridine (MPEP) or antisense-induced knock-down of mGlu5 receptors decreased the expression of the two main transcription factors that sustain ES cell self-renewal, i.e. Oct-4 and Nanog, as assessed by real-time PCR and immunoblotting [15].
  • In contrast to other pluripotent stem cell-specific genes such as Oct-4 and Nanog, the Ant4 gene was readily derepressed in differentiated cells after 5-aza-2'-deoxycytidine treatment [16].
  • The expression of ENK is markedly higher in undifferentiated ES cells than in retinoic acid differentiated ES cells and embryonic bodies [17].
  • To further evaluate the value of Dmp in opioid peptides, we investigated Dmp(1)-substituted analogues of the delta receptor ligands, deltorphin II (DLT: Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH(2)) and enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu) [18].

Physical interactions of Nanog


Regulatory relationships of Nanog


Other interactions of Nanog

  • Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of blastocysts, and transcription factors Oct-3/4, Nanog, Sox2, and STAT3, are essential for their self-renewal [22].
  • Oct4 and Nanog are transcription factors required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells [2].
  • Our analysis further suggested that the Nanog regulatory pathway was relatively independent of the LIF/Oct pathway and may interact with the Nodal/transforming growth factor-beta pathway [23].
  • The rapid down-regulation of Nanog mRNA during ESC differentiation correlates with the induction of p53 transcriptional activity and Ser 315 phosphorylation [5].
  • Reduction in Nanog expression correlated with induction of extraembryonic endoderm genes GATA4, GATA6, and laminin B1, with subsequent generation of groups of cells with parietal endoderm phenotype [24].
  • Our data demonstrate that the mSin3A-HDAC complex can positively regulate Nanog expression under proliferating conditions and that this activity is complementary to mSin3A-mediated p53-dependent silencing of Nanog during differentiation [25].

Analytical, diagnostic and therapeutic context of Nanog


  1. Differentiation of embryonic stem cells after transplantation into peritoneal cavity of irradiated mice and expression of specific germ cell genes in pluripotent cells. Gordeeva, O., Zinovieva, R., Smirnova, Y., Payushina, O., Nikonova, T., Khrushchov, N. Transplant. Proc. (2005) [Pubmed]
  2. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Loh, Y.H., Wu, Q., Chew, J.L., Vega, V.B., Zhang, W., Chen, X., Bourque, G., George, J., Leong, B., Liu, J., Wong, K.Y., Sung, K.W., Lee, C.W., Zhao, X.D., Chiu, K.P., Lipovich, L., Kuznetsov, V.A., Robson, P., Stanton, L.W., Wei, C.L., Ruan, Y., Lim, B., Ng, H.H. Nat. Genet. (2006) [Pubmed]
  3. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., Brivanlou, A.H. Nat. Med. (2004) [Pubmed]
  4. Regulatory networks in embryo-derived pluripotent stem cells. Boiani, M., Schöler, H.R. Nat. Rev. Mol. Cell Biol. (2005) [Pubmed]
  5. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Lin, T., Chao, C., Saito, S., Mazur, S.J., Murphy, M.E., Appella, E., Xu, Y. Nat. Cell Biol. (2005) [Pubmed]
  6. Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation. Gu, P., LeMenuet, D., Chung, A.C., Mancini, M., Wheeler, D.A., Cooney, A.J. Mol. Cell. Biol. (2005) [Pubmed]
  7. Nanog and transcriptional networks in embryonic stem cell pluripotency. Pan, G., Thomson, J.A. Cell Res. (2007) [Pubmed]
  8. Histone arginine methylation regulates pluripotency in the early mouse embryo. Torres-Padilla, M.E., Parfitt, D.E., Kouzarides, T., Zernicka-Goetz, M. Nature (2007) [Pubmed]
  9. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Strumpf, D., Mao, C.A., Yamanaka, Y., Ralston, A., Chawengsaksophak, K., Beck, F., Rossant, J. Development (2005) [Pubmed]
  10. Nanog expression in mouse germ cell development. Yamaguchi, S., Kimura, H., Tada, M., Nakatsuji, N., Tada, T. Gene Expr. Patterns (2005) [Pubmed]
  11. Aggregation of embryonic stem cells induces Nanog repression and primitive endoderm differentiation. Hamazaki, T., Oka, M., Yamanaka, S., Terada, N. J. Cell. Sci. (2004) [Pubmed]
  12. Pluripotential competence of cells associated with Nanog activity. Hatano, S.Y., Tada, M., Kimura, H., Yamaguchi, S., Kono, T., Nakano, T., Suemori, H., Nakatsuji, N., Tada, T. Mech. Dev. (2005) [Pubmed]
  13. Efficient gene transfer into mouse embryonic stem cells with adenovirus vectors. Kawabata, K., Sakurai, F., Yamaguchi, T., Hayakawa, T., Mizuguchi, H. Mol. Ther. (2005) [Pubmed]
  14. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4(+) stem cells identified in adult bone marrow. Kucia, M., Reca, R., Campbell, F.R., Zuba-Surma, E., Majka, M., Ratajczak, J., Ratajczak, M.Z. Leukemia (2006) [Pubmed]
  15. Endogenous activation of mGlu5 metabotropic glutamate receptors supports self-renewal of cultured mouse embryonic stem cells. Cappuccio, I., Spinsanti, P., Porcellini, A., Desiderati, F., De Vita, T., Storto, M., Capobianco, L., Battaglia, G., Nicoletti, F., Melchiorri, D. Neuropharmacology (2005) [Pubmed]
  16. DNA methylation is required for silencing of ant4, an adenine nucleotide translocase selectively expressed in mouse embryonic stem cells and germ cells. Rodić, N., Oka, M., Hamazaki, T., Murawski, M.R., Jorgensen, M., Maatouk, D.M., Resnick, J.L., Li, E., Terada, N. Stem Cells (2005) [Pubmed]
  17. A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially expressed in embryonic stem cells. Wang, S.H., Tsai, M.S., Chiang, M.F., Li, H. Gene Expr. Patterns (2003) [Pubmed]
  18. 2',6'-dimethylphenylalanine (Dmp) can mimic the N-terminal Tyr in opioid peptides. Sasaki, Y., Sasaki, A., Ariizumi, T., Igari, Y., Sato, K., Kohara, H., Niizuma, H., Ambo, A. Biol. Pharm. Bull. (2004) [Pubmed]
  19. Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Suzuki, A., Raya, A., Kawakami, Y., Morita, M., Matsui, T., Nakashima, K., Gage, F.H., Rodríguez-Esteban, C., Izpisúa Belmonte, J.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  20. The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency. Ma, T., Wang, Z., Guo, Y., Pei, D. J. Biol. Chem. (2009) [Pubmed]
  21. Cardiac myocyte differentiation: the Nkx2.5 and Cripto target genes in P19 clone 6 cells. Liu, H., Harris, T.M., Kim, H.H., Childs, G. Funct. Integr. Genomics (2005) [Pubmed]
  22. GABPalpha regulates Oct-3/4 expression in mouse embryonic stem cells. Kinoshita, K., Ura, H., Akagi, T., Usuda, M., Koide, H., Yokota, T. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  23. Conservation and variation of gene regulation in embryonic stem cells assessed by comparative genomics. Zhan, M., Miura, T., Xu, X., Rao, M.S. Cell Biochem. Biophys. (2005) [Pubmed]
  24. Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog. Hough, S.R., Clements, I., Welch, P.J., Wiederholt, K.A. Stem Cells (2006) [Pubmed]
  25. A positive regulatory role for the mSin3A-HDAC complex in pluripotency through Nanog and Sox2. Baltus, G.A., Kowalski, M.P., Tutter, A.V., Kadam, S. J. Biol. Chem. (2009) [Pubmed]
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