Homeobox protein NANOG

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See NANOG (computing) for the network operators' group.
Nanog homeobox
Identifiers
Symbol(s) NANOG;
External IDs OMIM: 607937 MGI: 1919200 HomoloGene: 78027
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 79923 71950
Ensembl ENSG00000111704 n/a
Uniprot Q9H9S0 n/a
Refseq NM_024865 (mRNA)
NP_079141 (protein)		 XM_132755 (mRNA)
XP_132755 (protein)
Location Chr 12: 7.83 - 7.84 Mb n/a
Pubmed search [6] [7]

NANOG (pron. nanOg) is a transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells.

Contents

[edit] Background information

[edit] Embryonic stem cells

NANOG is a gene expressed 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 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.

[edit] History

Dr Ian Chambers (currently of the Institute for Stem Cell Research, 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 Tir nan Og legend."[1]

[edit] Genes that code for NANOG

Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as OCT4, 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. [2] POU5F1 (OCT4), TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation. [3]

[edit] NANOG protein

Human NANOG protein (Accession number NP_079141) is a 305 amino acid protein with a conserved homeodomain motif that is localized to the nuclear component of cells. The homeodomain facilitates DNA binding.

There are N-terminal, homeodomain, and C-terminal region in human NANOG protein. Like murine NANOG, N-terminal region of human NANOG is rich in Ser, Thr and Pro residues and C-terminus contains W repeats. The homeodomain in hNANOG ranges from a.a.95 to a.a 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.

[edit] Current research

[edit] 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 (Chambers et al, 2003 and Mitsui et al, 2003)

Loss of Nanog function causes differentiation of embryonic stem cells into other cell types (Lin et al, 2005).

NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent.[4] Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[5]

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 embronic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis. (Lin et al, 2005)

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. (Piestun et al, 2006)

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.[6]

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.[7]

[edit] 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[8] and central nervous system (CNS).[9] Among germ cell tumors, NANOG is expressed by seminoma and embryonal carcinoma but not by mature teratoma nor endodermal sinus tumor[10]; 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;[9] expression of NANOG by other germ cell tumors of the CNS is unknown.

[edit] See also

[edit] Sources

  • New York Times "He has now applied the technique to human cells, starting with embryonic stem cells. The cells, he and colleagues say in the current issue of Cell, are controlled by a triumvirate of three transcription factors, known as oct4, sox2 and nanog.
  • MIT "The transcription factors Oct4, Sox2, and Nanog have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have, in collaboration with the Young lab, identified Oct4, Sox2, and Nanog target genes using genome-scale location analysis. We found, surprisingly, that Oct4, Sox2, and Nanog co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also show that Oct4, Sox2, and Nanog collaborate to form regulatory circuitry in ES cells consisting of autoregulatory and feedforward loops."
  • Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells
  • Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S and Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell May 30;113(5):643-55 (2003).
  • Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M and Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell May 30;113(5):631-42 (2003)
  • Lin TX, Chao C, Saito S, et al. P53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. NATURE CELL BIOLOGY 7 (2): 165-U80 FEB 2005.

[edit] External links

[edit] References

  1. ^ ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth. Retrieved on 2007-07-26.
  2. ^ Zhang X, Stojkovic P., Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M. Derivation of human embryonic stem cells from developing and arrested embryos. Stem Cells.[1]
  3. ^ Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S (2006). "Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan". Stem Cells Dev. 15 (4): 532–55. doi:10.1089/scd.2006.15.532. PMID 16978057. 
  4. ^ Darr H, Mayshar Y, Benvenisty N. Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development. 2006 Mar;133(6):1193-201.[2]
  5. ^ Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ. High-efficiency RNA interference in human embryonic stem cells. Stem Cells. 2005 Mar;23(3):299-305.[3]
  6. ^ Yates A, Chambers I. The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells. Biochem Soc Trans. 2005 Dec;33 (Pt 6):1518-21 [4]
  7. ^ Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, Vol 126, 663-676, 25 August 2006.[5]
  8. ^ Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology. 2005 Jul;47(1):48-56. PubMed
  9. ^ a b Santagata S, Hornick JL, Ligon KL. Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG. Am J Surg Pathol. 2006 Dec;30(12):1613-8. PubMed
  10. ^ Hart AH, Hartley L, Parker K, Ibrahim M, Looijenga LH, Pauchnik M, Chow CW, Robb L. The pluripotency homeobox gene NANOG is expressed in human germ cell tumors. Cancer. 2005 Nov 15;104(10):2092-8. PubMed

[edit] Further reading

  • Cavaleri F, Schöler HR (2003). "Nanog: a new recruit to the embryonic stem cell orchestra.". Cell 113 (5): 551–2. PMID 12787492. 
  • Constantinescu S (2004). "Stemness, fusion and renewal of hematopoietic and embryonic stem cells.". J. Cell. Mol. Med. 7 (2): 103–12. PMID 12927049. 
  • Pan G, Thomson JA (2007). "Nanog and transcriptional networks in embryonic stem cell pluripotency.". Cell Res. 17 (1): 42–9. doi:10.1038/sj.cr.7310125. PMID 17211451. 
  • Mitsui K, Tokuzawa Y, Itoh H, et al. (2003). "The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.". Cell 113 (5): 631–42. PMID 12787504. 
  • Chambers I, Colby D, Robertson M, et al. (2003). "Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.". Cell 113 (5): 643–55. PMID 12787505. 
  • Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
  • Clark AT, Rodriguez RT, Bodnar MS, et al. (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. PMID 14990856. 
  • Hart AH, Hartley L, Ibrahim M, Robb L (2004). "Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human.". Dev. Dyn. 230 (1): 187–98. doi:10.1002/dvdy.20034. PMID 15108323. 
  • Booth HA, Holland PW (2005). "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, et al. (2005). "Pluripotential competence of cells associated with Nanog activity.". Mech. Dev. 122 (1): 67–79. doi:10.1016/j.mod.2004.08.008. PMID 15582778. 
  • Deb-Rinker P, Ly D, Jezierski A, et al. (2005). "Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation.". J. Biol. Chem. 280 (8): 6257–60. doi:10.1074/jbc.C400479200. PMID 15615706. 
  • Zaehres H, Lensch MW, Daheron L, et al. (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, et al. (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, et al. (2006). "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, et al. (2005). "Identification of a putative transactivation domain in human Nanog.". Exp. Mol. Med. 37 (3): 250–4. PMID 16000880. 
  • Boyer LA, Lee TI, Cole MF, et al. (2005). "Core transcriptional regulatory circuitry in human embryonic stem cells.". Cell 122 (6): 947–56. doi:10.1016/j.cell.2005.08.020. PMID 16153702. 
  • Kim JS, Kim J, Kim BS, et al. (2006). "Identification and functional characterization of an alternative splice variant within the fourth exon of human nanog.". Exp. Mol. Med. 37 (6): 601–7. PMID 16391521. 
  • Darr H, Mayshar Y, Benvenisty N (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. 
v • d • e
Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP)
Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • BATF • BLZF1 • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3, L1) • CREM • DBP • DDIT3 • GABPA • HLF • MAF (B, F, G, K) • NFE (2, L1, L2) • NRL • NRF1 • XBP1
(1.2) Basic helix-loop-helix (bHLH)
ATOH1 • AhR • AHRR • ARNT • ASCL1 • BHLHB2 • BMAL (ARNTL, ARNTL2) • CLOCK • EPAS1 • HAND (1, 2) • HES (5, 6) • HEY (1, 2, L) • HES1 • HIF (1A, 3A) • ID (1, 2, 3, 4) • LYL1 • MXD4 • MYCL1 • MYCN • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • Neurogenins • NeuroD (1, 2) • NPAS (1, 2, 3) • OLIG (1, 2) • Scleraxis • TAL1 • Twist • USF1
(1.3) bHLH-ZIP
MAX • MITF • MNT • MLX • MXI1 • Myc • SREBP (1, 2)
(1.6) Basic helix-span-helix (bHSH)
(2) Zinc finger
DNA-binding domains
(2.1) Nuclear receptor (Cys4)
subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
(2.2) Other Cys4
GATA (1, 2, 3, 4, 5, 6) • MTA (1, 2, 3)
(2.3) Cys2His2
ATBF1 • BCL(6, 11A, 11B) • CTCF • E4F1 • EGR (2, 3) • ERV3 • General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF: 1, 2, TFIIH: 1, 2, 4, 2I, 3A, 3C1, 3C2) • GFI1 • GLI-Krüppel family (1, 2, 3, YY1) • HIC (1, 2) • HIVEP (1, 2, 3) • IKZF (1, 2, 3) • ILF (2, 3) • KLF (2, 4, 5, 6, 9, 10, 11, 12, 13) • MTF1 • MYT1 • OSR1 • Sp1 • zinc finger ((3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 318, 330, 346, 350, 365, 366, 384, 451, 452, 471, 593, 638, 649, 655) • Zbtb7 (7A) • ZBT (16, 17, 33)
(2.4) Cys6
(2.5) Alternating composition
AIRE • DIDO1 • GRLF1 • ING (1, 2, 4) • JARID (1A, 1B, 1C, 1D, 2) • JMJD1B
(3) Helix-turn-helix
domains
ARX • CDX (1, 2) • CRX • CUTL1 • DLX (3, 4, 5) • EMX2 • EN (1, 2) • FHL (1, 2, 3) • HESX1 • HHEX • HLX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) • HOPX • MEIS (1, 2) • MEOX2 • MNX1 • MSX (1, 2) • NANOG • NKX (2-1, 2-5, 3-1) • PHF (3, 6, 10, 17) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7) • OTX (1, 2) • PDX1
(3.2) Paired box
PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, K2, L2, M1, N3, O1A, , O3A, O4, P1, P2, P3)
HSF (1, 2, 4)
(3.5) Tryptophan clusters
ELF (4, 5) • EGF • ELK (1, 3, 4) • ERF • ERG • ETS (1, 2) • ETV (1, 4, 5, 6) • FLI1 • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB • MYBL2
(3.6) TEA domain
transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with
minor groove contacts
(4.1) Rel homology region
NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (C1, C2, C3, C4, 5)
(4.2) STAT
STAT (1, 2, 3, 4, 5, 6)
(4.3) p53
(4.4) MADS box
Mef2 (A, B, C, D) • SRF
HNF (1A, 1B) • LEF1 • SOX (2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 15, 18) • SRY • SSRP1
(4.10) Cold-shock domain
(4.11) Runt
(0) Other
transcription factors
(0.2) HMGI(Y)
HMGA (1, 2) • HBP1
Rb • RBL1 • RBL2
(0.5) AP-2/EREBP-related factors
Apetala 2 • EREBP • B3
(0.6) Miscellaneous
ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • IFI (16, 35) • MLL (2, 3, T1) • MNDA • NFI (A, B, C, X) • NFY (A, B, C) • Rho/Sigma • R-SMAD
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