Homeobox protein NANOG

See NANOG (computing) for the network operators' group.
Nanog homeobox
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol NANOG
External IDs OMIM: 607937 MGI: 1919200 HomoloGene: 78027 GeneCards: NANOG Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 79923 71950
Ensembl ENSG00000111704 ENSMUSG00000012396
UniProt Q9H9S0 Q80Z64
RefSeq (mRNA) NM_001297698 NM_001289828
RefSeq (protein) NP_001284627 NP_001276757
Location (UCSC) Chr 12:
7.79 – 7.8 Mb		 Chr 6:
122.71 – 122.71 Mb
PubMed search

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.[1][2]

Structure

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

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:

These markers allowed for the differentiation in vitro and in vivo conditions into derivatives of all three germ layers.[3]

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[4]

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.[5]

Current research

Molecular biology

Overexpression of Nanog in mouse embryonic stem cells causes them to self-renew in the absence of Leukemia inhibitory factor. In the absence of Nanog, mouse embryonic stem cells differentiate into visceral/parietal endoderm.[1][2] Loss of Nanog function causes differentiation of mouse embryonic stem cells into other cell types.[6]

NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent.[7] Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[8]

It has been shown that the tumour suppressor p53 binds to the promoter of NANOG and suppresses its expression after DNA damage in mouse embryonic stem cells. p53 can thus induce differentiation of embryonic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis.[6]

Nanog transforms NIH3T3 cells. By using DNA microarray to find the transcription targets of Nanog, Nanog regulated genes have been identified. Some of these target genes explain the transformation of NIH3T3 cells.[9]

GATA6 and Nanog have been linked due to the similar cellular differentiation of ES cells in their absence, which leads to the hypothesis that Nanog may prevent ectodermal growth via repressing GATA6.[10]

Yamanaka et al., demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Of these four factors it has been shown that Nanog was dispensable for such induction in this cell system.[11]

Clinical medicine

NANOG may be useful in the immunohistochemical diagnosis of tumors. NANOG is expressed in germ cells of the fetus and in some germ cell tumors of the gonads[12] and central nervous system (CNS).[13][14] Expression of NANOG by immature teratoma and choriocarcinoma is unknown. Among tumors usually found in the CNS, NANOG is expressed by germinoma (a germ cell tumor histologically identical to seminoma and dysgerminoma) but not by pineoblastoma, lymphoma, pituitary adenoma and gliomas;[13] expression of NANOG by other germ cell tumors of the CNS is unknown. Recent studies have suggested that NANOG could define cancer stem cells in several types of solid tumors such as colorectal cancer [15]

Evolutionary biology

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.[16]

Biophysics

Based on high-resolution nucleosome mapping in mouse embryonic stem cells, it has been proposed that as a pioneering factor, Nanog is able to bind the DNA inside the nucleosome in vivo.[17]

Name

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."[18]

See also

References

  1. 1 2 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.
  2. 1 2 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (Feb 2005). "p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression". Nature Cell Biology 7 (2): 165–71. doi:10.1038/ncb1211. PMID 15619621.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Piestun D, Kochupurakkal BS, Jacob-Hirsch J, Zeligson S, Koudritsky M, Domany E, Amariglio N, Rechavi G, Givol D (Apr 2006). "Nanog transforms NIH3T3 cells and targets cell-type restricted genes". Biochemical and Biophysical Research Communications 343 (1): 279–85. doi:10.1016/j.bbrc.2006.02.152. PMID 16540082.
  10. ↑ Yates A, Chambers I (Dec 2005). "The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells". Biochemical Society Transactions 33 (Pt 6): 1518–21. doi:10.1042/BST20051518. PMID 16246159.
  11. ↑ Takahashi K, Yamanaka S (Aug 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  12. ↑ 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.
  13. 1 2 Santagata S, Hornick JL, Ligon KL (Dec 2006). "Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG". The American Journal of Surgical Pathology 30 (12): 1613–8. doi:10.1097/01.pas.0000213320.04919.1a. PMID 17122519.
  14. ↑ Hart AH, Hartley L, Parker K, Ibrahim M, Looijenga LH, Pauchnik M, Chow CW, Robb L (Nov 2005). "The pluripotency homeobox gene NANOG is expressed in human germ cell tumors". Cancer 104 (10): 2092–8. doi:10.1002/cncr.21435. PMID 16206293.
  15. ↑ Ibrahim EE, Babaei-Jadidi R, Saadeddin A, Spencer-Dene B, Hossaini S, Abuzinadah M, Li N, Fadhil W, Ilyas M, Bonnet D, Nateri AS (Oct 2012). "Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms". Stem Cells 30 (10): 2076–87. doi:10.1002/stem.1182. PMID 22851508.
  16. ↑ 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.
  17. ↑ Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K (Nov 2012). "Genome-wide nucleosome positioning during embryonic stem cell development". Nature Structural & Molecular Biology 19 (11): 1185–92. doi:10.1038/nsmb.2419. PMID 23085715.
  18. ↑ "ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth". Retrieved 2007-07-26.

Further reading

  • 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. 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. 

External links

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