Homeobox protein NANOG
Homeobox protein NANOG(hNanog)is atranscriptionalfactor that helpsembryonic stem cells(ESCs) maintainpluripotencyby suppressingcell determination factors.[5]hNanog is encoded in humans by theNANOGgene. Several types of cancer are associated withNANOG.[6]
Etymology
[edit]The name NANOG derives fromTír na nÓg(Irish for "Land of the Young" ), a name given to the Celtic Otherworld in Irish and Scottish mythology.[7][8]
Structure
[edit]The human hNanog protein coded by theNANOGgene, consists of 305 amino acids and possesses 3 functional domains: the N-terminal domain, the C- terminal domain, and the conservedhomeodomainmotif. The homeodomain region facilitates DNA binding. TheNANOGis located on chromosome 12, and the mRNA contains a 915 bpopen reading frame(ORF) with 4 exons and 3 introns.[8]
The N-terminal region of hNanog is rich inserine,threonineandprolineresidues, and the C-terminus contains atryptophan-rich domain. The homeodomain in hNANOG ranges from residues 95 to 155. There are also additional NANOG genes (NANOG2, NANOG p8) which potentially affect ESCs' differentiation. Scientists have shown thatNANOGis fundamental for self-renewal and pluripotency, and NANOG p8 is highly expressed in cancer cells.[9]
Function
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Transcription_programs_in_stem_cells..jpg/220px-Transcription_programs_in_stem_cells..jpg)
NANOG is a transcription factor inembryonic stem cells(ESCs) and is thought to be a key factor in maintainingpluripotency.NANOG is thought to function in concert with other factors such asPOU5F1 (Oct-4)andSOX2to 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.
NANOG has been described to be expressed in the posterior side of the epiblast at the onset of gastrulation.[10]There, NANOG has been implicated in inhibiting embryonic hematopoiesis by repressing the expression of the transcription factorTal1.[11]In this embryonic stage, NANOG repressesPou3f1,a transcription factor crucial for the anterior-posterior axis formation.[10]
Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such asPOU5F1,NANOG andRex1.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 differentiationin vitroandin vivoconditions into derivatives of all three germ layers.[12]
POU5F1,TDGF1 (CRIPTO),SALL4,LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[13]
The NANOG protein has been found to be a transcriptional activator for theRex1promoter, playing a key role in sustainingRex1expression. Knockdown of NANOG inembryonic stem cellsresults in a reduction ofRex1expression, while forced expression of NANOG stimulatesRex1expression.[14]
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.[15][16][17][18][19]
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.[20][21][22]
Recent research has shown that the localization of NANOG and other transcription factors have potential consequences on cellular function. Experimental evidence has shown that the level of NANOG p8 expression is elevated specially in cancer cells, which mean that NANOG p8 gene is a critical member in (CSCs) Cancer stem cells, so knocking it down could reduce the cancer malignancy.[9]
Diagnostics
[edit]NANOG p8 gene has been evaluated as a prognostic and predictive cancer biomarker.[23]
Cancer stem cells
[edit]Nanog is atranscription factorthat controls both self-renewal andpluripotencyofembryonic stem cells.Similarly, the expression of Nanog family proteins is increased in many types of cancer and correlates with a worse prognosis.[9]
Evolution
[edit]Humansandchimpanzeesshare ten NANOGpseudogenes(NanogP2-P11) during evaluation, two of them are located on the X chromosome and they characterized by the 5’ promoter sequences and the absence of introns as a result of mRNA retrotransposition[8]all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack thepoly-(A) tailscharacteristic of most retropseudogenes, indicating that 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 unrelatedgenomes,evolutionary biologistspoint to NANOG and its pseudogenes as providingevidence of common descentbetween humans and chimpanzees.[24]
See also
[edit]- Enhancer
- Histone
- Oct-4
- Pribnow box
- Promoter
- RNA polymerase
- Brachyury
- Transcription factors
- Gene regulatory network
- Bioinformatics
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000111704–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000012396–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^Heurtier, V., Owens, N., Gonzalez, I. et al. The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells. Nat Commun 10, 1109 (2019).https://doi.org/10.1038/s41467-019-09041-z
- ^Grubelnik G, Boštjančič E, Pavlič A, Kos M, Zidar N (March 2020)."NANOG expression in human development and cancerogenesis".Experimental Biology and Medicine.245(5): 456–464.doi:10.1177/1535370220905560.PMC7082888.PMID32041418.
- ^"ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth".Retrieved2007-07-26.
- ^abcGawlik-Rzemieniewska N, Bednarek I (2015-11-30)."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.PMC4848008.PMID26618281.
- ^abcZhang W, Sui Y, Ni J, Yang T (2016)."Insights into theNanoggene: A propeller for stemness in primitive stem cells ".International Journal of Biological Sciences.12(11): 1372–1381.doi:10.7150/ijbs.16349.PMC5118783.PMID27877089.
- ^abBarral A, Rollan I, Sanchez-Iranzo H, Jawaid W, Badia-Careaga C, Menchero S, et al. (December 2019)."NanogregulatesPou3f1expression at the exit from pluripotency during gastrulation ".Biology Open.8(11): bio046367.doi:10.1242/bio.046367.PMC6899006.PMID31791948.
- ^Sainz de Aja J, Menchero S, Rollan I, Barral A, Tiana M, Jawaid W, et al. (April 2019)."The pluripotency factor NANOG controls primitive hematopoiesis and directly regulatesTal1".The EMBO Journal.38(7).doi:10.15252/embj.201899122.PMC6443201.PMID30814124.
- ^Zhang X, Stojkovic P, Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M (December 2006)."Derivation of human embryonic stem cells from developing and arrested embryos".Stem Cells.24(12): 2669–2676.doi:10.1634/stemcells.2006-0377.PMID16990582.S2CID32587408.
- ^Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S (August 2006). "Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan".Stem Cells and Development.15(4): 532–555.doi:10.1089/scd.2006.15.532.PMID16978057.
- ^Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D (August 2006)."Regulation of the pluripotency marker Rex-1 by Nanog and Sox2".The Journal of Biological Chemistry.281(33): 23319–23325.doi:10.1074/jbc.M601811200.PMID16714766.
- ^Shahini A, Choudhury D, Asmani M, Zhao R, Lei P, Andreadis ST (January 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.PMID29245050.
- ^Shahini A, Mistriotis P, Asmani M, Zhao R, Andreadis ST (June 2017)."NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues".Tissue Engineering. Part A.23(11–12): 535–545.doi:10.1089/ten.TEA.2016.0494.PMC5467120.PMID28125933.
- ^Mistriotis P, Bajpai VK, Wang X, Rong N, Shahini A, Asmani M, et al. (January 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.PMID27350449.S2CID4482665.
- ^Han J, Mistriotis P, Lei P, Wang D, Liu S, Andreadis ST (December 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.PMC3508087.PMID22949105.
- ^Münst B, Thier MC, Winnemöller D, Helfen M, Thummer RP, Edenhofer F (March 2016)."Nanog induces suppression of senescence through downregulation of p27KIP1 expression".Journal of Cell Science.129(5): 912–920.doi:10.1242/jcs.167932.PMC4813312.PMID26795560.
- ^Gong S, Li Q, Jeter CR, Fan Q, Tang DG, Liu B (September 2015)."Regulation of NANOG in cancer cells".Molecular Carcinogenesis.54(9): 679–687.doi:10.1002/mc.22340.PMC4536084.PMID26013997.
- ^Jeter CR, Yang T, Wang J, Chao HP, Tang DG (August 2015)."Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions".Stem Cells.33(8): 2381–2390.doi:10.1002/stem.2007.PMC4509798.PMID25821200.
- ^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.PMC4848008.PMID26618281.
- ^Iv Santaliz-Ruiz LE, Xie X, Old M, Teknos TN, Pan Q (December 2014)."Emerging role of nanog in tumorigenesis and cancer stem cells".International Journal of Cancer.135(12): 2741–2748.doi:10.1002/ijc.28690.PMC4065638.PMID24375318.
- ^Fairbanks DJ (2007).Relics of Eden: The Powerful Evidence of Evolution in Human DNA.Buffalo, N.Y: Prometheus Books. pp. 94–96, 177–182.ISBN978-1-59102-564-1.
Further reading
[edit]- Cavaleri F, Schöler HR (May 2003)."Nanog: a new recruit to the embryonic stem cell orchestra".Cell.113(5): 551–552.doi:10.1016/S0092-8674(03)00394-5.PMID12787492.S2CID16254995.
- Constantinescu S (2004)."Stemness, fusion and renewal of hematopoietic and embryonic stem cells".Journal of Cellular and Molecular Medicine.7(2): 103–112.doi:10.1111/j.1582-4934.2003.tb00209.x.PMC6740230.PMID12927049.
- Pan G, Thomson JA (January 2007)."Nanog and transcriptional networks in embryonic stem cell pluripotency".Cell Research.17(1): 42–49.doi:10.1038/sj.cr.7310125.PMID17211451.
- Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, et al. (May 2003)."The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells".Cell.113(5): 631–642.doi:10.1016/S0092-8674(03)00393-3.PMID12787504.S2CID18836242.
- 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): 643–655.doi:10.1016/S0092-8674(03)00392-1.hdl:1842/843.PMID12787505.S2CID2236779.
- Clark AT, Rodriguez RT, Bodnar MS, Abeyta MJ, Cedars MI, Turek PJ, 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): 169–179.doi:10.1634/stemcells.22-2-169.PMID14990856.S2CID38136098.
- 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): 187–198.doi:10.1002/dvdy.20034.PMID15108323.S2CID21502533.
- Booth HA, Holland PW (August 2004). "Eleven daughters of NANOG".Genomics.84(2): 229–238.doi:10.1016/j.ygeno.2004.02.014.PMID15233988.
- Hatano SY, Tada M, Kimura H, Yamaguchi S, Kono T, Nakano T, et al. (January 2005). "Pluripotential competence of cells associated with Nanog activity".Mechanisms of Development.122(1): 67–79.doi:10.1016/j.mod.2004.08.008.hdl:2433/144766.PMID15582778.S2CID17490059.
- Deb-Rinker P, Ly D, Jezierski A, Sikorska M, Walker PR (February 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): 6257–6260.doi:10.1074/jbc.C400479200.PMID15615706.
- Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (March 2005)."High-efficiency RNA interference in human embryonic stem cells".Stem Cells.23(3): 299–305.doi:10.1634/stemcells.2004-0252.PMID15749924.S2CID1395518.
- Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, et al. (July 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.PMID15982323.S2CID10164525.
- Hyslop L, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S, et al. (September 2005)."Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages".Stem Cells.23(8): 1035–1043.doi:10.1634/stemcells.2005-0080.PMID15983365.S2CID29881293.
- Oh JH, Do HJ, Yang HM, Moon SY, Cha KY, Chung HM, Kim JH (June 2005)."Identification of a putative transactivation domain in human Nanog".Experimental & Molecular Medicine.37(3): 250–254.doi:10.1038/emm.2005.33.PMID16000880.
- Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. (September 2005)."Core transcriptional regulatory circuitry in human embryonic stem cells".Cell.122(6): 947–956.doi:10.1016/j.cell.2005.08.020.PMC3006442.PMID16153702.
- Kim JS, Kim J, Kim BS, Chung HY, Lee YY, Park CS, et al. (December 2005)."Identification and functional characterization of an alternative splice variant within the fourth exon of human nanog".Experimental & Molecular Medicine.37(6): 601–607.doi:10.1038/emm.2005.73.PMID16391521.
- Darr H, Mayshar Y, Benvenisty N (March 2006)."Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features".Development.133(6): 1193–1201.doi:10.1242/dev.02286.PMID16501172.
- Saunders A, Li D, Faiola F, Huang X, Fidalgo M, Guallar D, et al. (May 2017)."Context-Dependent Functions of NANOG Phosphorylation in Pluripotency and Reprogramming".Stem Cell Reports.8(5): 1115–1123.doi:10.1016/j.stemcr.2017.03.023.PMC5425684.PMID28457890.
External links
[edit]- NANOG+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- Nanog+protein,+mouseat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- FactorBookNANOG
- "Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells".Young Lab.Whitehead Institute for Biomedical Research. Archived fromthe originalon 2009-06-28.Retrieved2009-02-28.
- "Jaenisch Lab Research Summary".Whitehead Institute. Archived fromthe originalon 2012-06-26.Retrieved2009-02-28.
- Discovery reveals more about stem cells' immortality