NANOG (medicine)

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3-D Structure of the Nanog Homeobox. [1]
Nanog homeobox
Identifiers
Symbol NANOG
Entrez 79923
HUGO 20857
OMIM 607937
RefSeq NM_024865
UniProt Q9H9S0
Other data
Locus Chr. 12 p13.31

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Overview

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

Background information

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 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.

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."[2]

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. [3] POU5F1 (OCT4), TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation. [4]

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.

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 (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.[5] Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[6]

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 has been identified . Some of these target genes explain the transformation of IH3T3. (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.[7]

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.[8]

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[9] and central nervous system (CNS).[10] Among germ cell tumors, NANOG is expressed by seminoma and embryonal carcinoma but not by mature teratoma nor endodermal sinus tumor[11]; 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;[10] expression of NANOG by other germ cell tumors of the CNS is unknown.

See also

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.

External links

References

  1. ModBase: homeobox transcription factor nanog[1]
  2. ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth. Retrieved on 2007-07-26.
  3. 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.[2]
  4. 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.
  5. 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.[3]
  6. 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.[4]
  7. 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 [5]
  8. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, Vol 126, 663-676, 25 August 2006.[6]
  9. 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
  10. 10.0 10.1 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
  11. 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
cs:Nanog

sk:Nanog



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