Homeobox protein NANOG

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NANOG
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNANOG, entrez:79923, Nanog, Nanog homeobox
External IDsOMIM: 607937 MGI: 1919200 HomoloGene: 78027 GeneCards: NANOG
Gene location (Human)
Chromosome 12 (human)
Chr.Chromosome 12 (human)[1]
Chromosome 12 (human)
Genomic location for NANOG
Genomic location for NANOG
Band12p13.31Start7,787,794 bp[1]
End7,799,141 bp[1]
RNA expression pattern
PBB GE NANOG 220184 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

79923

71950

Ensembl

ENSG00000111704

ENSMUSG00000012396

UniProt

Q9H9S0

Q80Z64

RefSeq (mRNA)

NM_001297698
NM_024865

NM_028016
NM_001289828
NM_001289830
NM_001289831

RefSeq (protein)

NP_001284627
NP_079141

NP_001276757
NP_001276759
NP_001276760
NP_082292

Location (UCSC)Chr 12: 7.79 – 7.8 MbChr 6: 122.71 – 122.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

NANOG (pron. nanOg) is a transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells. In humans, this protein is encoded by the NANOG gene.[5][6]

Structure[edit]

Human NANOG protein is a 305 amino acid protein with a conserved homeodomain motif that is localized to the nuclear component of cells. The homeodomain region facilitates DNA binding.

There are N-terminal, homeodomain, and C-terminal regions in human NANOG protein. Like murine NANOG, the N-terminal region of human NANOG is rich in Ser, Thr and Pro residues, and the C-terminus contains W repeats. The homeodomain in hNANOG ranges from residues 95 to 155. The conserved sequence of homeodomain are a.a. 99-100, 102, 106-107, 110, 114, 119, 121, 127-128, 132, 134, 138-140, 142-145, 147, 149, and 151-152.

Function[edit]

Transcription programs in embryonic stem cells

NANOG is a transcription factor in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency. NANOG is thought to function in concert with other factors such as POU5F1 (Oct-4) and SOX2 to establish ESC identity. These cells offer an important area of study because of their ability to maintain pluripotency. In other words, these cells have the ability to become virtually any cell of any of the three germ layers (endoderm, ectoderm, mesoderm). It is for this reason that understanding the mechanisms that maintain a cell's pluripotency is critical for researchers to understand how stem cells work; and may lead to future advances in treating degenerative diseases.

Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as POU5F1, NANOG and Rex1. Derived human ESC lines also expressed specific pluripotency markers:

  • TRA-1-60
  • TRA-1-81
  • SSEA4
  • alkaline phosphatase
  • TERT
  • Rex1

These markers allowed for the differentiation in vitro and in vivo conditions into derivatives of all three germ layers.[7]

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[8]

The NANOG protein has been found to be a transcriptional activator for the Rex1 promoter, playing a key role in sustaining Rex1 expression. Knockdown of NANOG in embryonic stem cells results in a reduction of Rex1 expression, while forced expression of NANOG stimulates Rex1 expression.[9]

Besides the effects of NANOG in the embryonic stages of life, ectopic expression of NANOG in the adult stem cells can restore the proliferation and differentiation potential that is lost due to organismal aging or cellular senescence.[10][11][12][13][14]

Clinical significance[edit]

Cancer[edit]

NANOG is highly expressed in cancer stem cells and may thus function as an oncogene to promote carcinogenesis. High expression of NANOG correlates with poor survival in cancer patients.[15][16][17]

Diagnostics[edit]

NANOG has been evaluated as a prognostic and predictive cancer biomarker.[18]

Evolution[edit]

Humans and chimpanzees share ten NANOG pseudogenes, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the poly-(A) tails characteristic of most retropseudogenes, indicating copying errors occurred during their creation. Due to the high improbability that the same pseudogenes (copying errors included) would exist in the same places in two unrelated genomes, evolutionary biologists point to NANOG and its pseudogenes as providing formidable evidence of common descent between humans and chimpanzees.[19]

Name[edit]

Professor Ian Chambers (currently of the MRC Centre for Regenerative Medicine, The University of Edinburgh, UK) who isolated the mouse Nanog gene said: "Nanog seems to be a master gene that makes embryonic stem cells grow in the laboratory. In effect this makes stem cells immortal. Being Scottish, I therefore chose the name after the Tír na nÓg legend."[20]

See also[edit]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000111704 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000012396 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (May 2003). "The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells". Cell. 113 (5): 631–42. doi:10.1016/S0092-8674(03)00393-3. PMID 12787504. 
  6. ^ Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (May 2003). "Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells". Cell. 113 (5): 643–55. doi:10.1016/S0092-8674(03)00392-1. PMID 12787505. 
  7. ^ Zhang X, Stojkovic P, Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M (Dec 2006). "Derivation of human embryonic stem cells from developing and arrested embryos". Stem Cells. 24 (12): 2669–76. doi:10.1634/stemcells.2006-0377. PMID 16990582. 
  8. ^ Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S (Aug 2006). "Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan". Stem Cells and Development. 15 (4): 532–55. doi:10.1089/scd.2006.15.532. PMID 16978057. 
  9. ^ Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D (Aug 2006). "Regulation of the pluripotency marker Rex-1 by Nanog and Sox2". The Journal of Biological Chemistry. 281 (33): 23319–25. doi:10.1074/jbc.M601811200. PMID 16714766. 
  10. ^ Shahini A, Choudhury D, Asmani M, Zhao R, Lei P, Andreadis S (Jan 2018). "NANOG restores the impaired myogenic differentiation potential of skeletal myoblasts after multiple population doublings". Stem Cell Research. 26: 55–66. doi:10.1016/j.scr.2017.11.018. PMID 29245050. 
  11. ^ Shahini A, Mistriotis P, Asmani M, Zhao R, Andreadis S (Jun 2017). "NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues". Tissue Eng Part A. 23 (11-12): 535–545. doi:10.1089/ten.TEA.2016.0494. PMID 28125933. 
  12. ^ Mistriotis P, Bajpai V, Wang X, Rong N, Shahini A, Asmani M, Liang M, Wang J, Lei P, Liu S, Zhao R, Andreadis S (Jan 2017). "NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression". Stem Cells. 35 (1): 207–221. doi:10.1002/stem.2452. PMID 27350449. 
  13. ^ Han J, Mistriotis P, Lei P, Wang D, Liu S, Zhao R, Andreadis S (Dec 2012). "Nanog Reverses the Effects of Organismal Aging on Mesenchymal Stem Cell Proliferation and Myogenic Differentiation Potential". Stem Cells. 30 (12): 2746–2759. doi:10.1002/stem.1223. PMC 3508087 Freely accessible. PMID 22949105. 
  14. ^ Munst B, Thier M, Winnemoller D, Helfen M, Thummer R, Edenhofer F (Jan 2016). "Nanog induces suppression of senescence through downregulation of p27KIP1 expression". Journal of Cell Science. 129 (5): 912–20. doi:10.1242/jcs.167932. PMC 4813312 Freely accessible. PMID 26795560. 
  15. ^ Gong S, Li Q, Jeter CR, Fan Q, Tang DG, Liu B (2015). "Regulation of NANOG in cancer cells". Molecular Carcinogenesis. 54 (9): 679–87. doi:10.1002/mc.22340. PMC 4536084 Freely accessible. PMID 26013997. 
  16. ^ Jeter CR, Yang T, Wang J, Chao HP, Tang DG (2015). "Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions". Stem Cells (Dayton, Ohio). 33 (8): 2381–90. doi:10.1002/stem.2007. PMC 4509798 Freely accessible. PMID 25821200. 
  17. ^ Gawlik-Rzemieniewska N, Bednarek I (2016). "The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells". Cancer Biology & Therapy. 17 (1): 1–10. doi:10.1080/15384047.2015.1121348. PMC 4848008 Freely accessible. PMID 26618281. 
  18. ^ Iv Santaliz-Ruiz LE, Xie X, Old M, Teknos TN, Pan Q (2014). "Emerging role of nanog in tumorigenesis and cancer stem cells". International Journal of Cancer. 135 (12): 2741–8. doi:10.1002/ijc.28690. PMC 4065638 Freely accessible. PMID 24375318. 
  19. ^ Daniel J. Fairbanks (2007). Relics of Eden: The Powerful Evidence of Evolution in Human DNA. Buffalo, N.Y: Prometheus Books. pp. 94–96, 177–182. ISBN 1-59102-564-8. 
  20. ^ "ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth". Retrieved 2007-07-26. 

Further reading[edit]

  • Cavaleri F, Schöler HR (May 2003). "Nanog: a new recruit to the embryonic stem cell orchestra". Cell. 113 (5): 551–2. doi:10.1016/S0092-8674(03)00394-5. PMID 12787492. 
  • Constantinescu S (2004). "Stemness, fusion and renewal of hematopoietic and embryonic stem cells". Journal of Cellular and Molecular Medicine. 7 (2): 103–12. doi:10.1111/j.1582-4934.2003.tb00209.x. PMID 12927049. 
  • Pan G, Thomson JA (Jan 2007). "Nanog and transcriptional networks in embryonic stem cell pluripotency". Cell Research. 17 (1): 42–9. doi:10.1038/sj.cr.7310125. PMID 17211451. 
  • Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (May 2003). "The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells". Cell. 113 (5): 631–42. doi:10.1016/S0092-8674(03)00393-3. PMID 12787504. 
  • Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (May 2003). "Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells". Cell. 113 (5): 643–55. doi:10.1016/S0092-8674(03)00392-1. PMID 12787505. 
  • Clark AT, Rodriguez RT, Bodnar MS, Abeyta MJ, Cedars MI, Turek PJ, Firpo MT, Reijo Pera RA (2004). "Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma". Stem Cells. 22 (2): 169–79. doi:10.1634/stemcells.22-2-169. PMID 14990856. 
  • Hart AH, Hartley L, Ibrahim M, Robb L (May 2004). "Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human". Developmental Dynamics. 230 (1): 187–98. doi:10.1002/dvdy.20034. PMID 15108323. 
  • Booth HA, Holland PW (Aug 2004). "Eleven daughters of NANOG". Genomics. 84 (2): 229–38. doi:10.1016/j.ygeno.2004.02.014. PMID 15233988. 
  • Hatano SY, Tada M, Kimura H, Yamaguchi S, Kono T, Nakano T, Suemori H, Nakatsuji N, Tada T (Jan 2005). "Pluripotential competence of cells associated with Nanog activity". Mechanisms of Development. 122 (1): 67–79. doi:10.1016/j.mod.2004.08.008. PMID 15582778. 
  • Deb-Rinker P, Ly D, Jezierski A, Sikorska M, Walker PR (Feb 2005). "Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation". The Journal of Biological Chemistry. 280 (8): 6257–60. doi:10.1074/jbc.C400479200. PMID 15615706. 
  • Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (Mar 2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells. 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924. 
  • Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E (Jul 2005). "Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours". Histopathology. 47 (1): 48–56. doi:10.1111/j.1365-2559.2005.02182.x. PMID 15982323. 
  • Hyslop L, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S, Herbert M, Murdoch A, Strachan T, Lako M (Sep 2005). "Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages". Stem Cells. 23 (8): 1035–43. doi:10.1634/stemcells.2005-0080. PMID 15983365. 
  • Oh JH, Do HJ, Yang HM, Moon SY, Cha KY, Chung HM, Kim JH (Jun 2005). "Identification of a putative transactivation domain in human Nanog". Experimental & Molecular Medicine. 37 (3): 250–4. doi:10.1038/emm.2005.33. PMID 16000880. 
  • 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 (Sep 2005). "Core transcriptional regulatory circuitry in human embryonic stem cells". Cell. 122 (6): 947–56. doi:10.1016/j.cell.2005.08.020. PMC 3006442 Freely accessible. PMID 16153702. 
  • Kim JS, Kim J, Kim BS, Chung HY, Lee YY, Park CS, Lee YS, Lee YH, Chung IY (Dec 2005). "Identification and functional characterization of an alternative splice variant within the fourth exon of human nanog". Experimental & Molecular Medicine. 37 (6): 601–7. doi:10.1038/emm.2005.73. PMID 16391521. 
  • Darr H, Mayshar Y, Benvenisty N (Mar 2006). "Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features". Development. 133 (6): 1193–201. doi:10.1242/dev.02286. PMID 16501172. 
  • Saunders A, Wang J (Mar 2006). "Context-Dependent Functions of NANOG Phosphorylation in Pluripotency and Reprogramming". Stem Cell Reports. doi:10.1016/j.stemcr.2017.03.023. 

External links[edit]

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