POU5F1 (OCT4), SOX2, and NANOG bind elements in the promoters of target genes. The target genes of each transcription factor overlap extensively: POU5F1, SOX2, and NANOG co-occupy at least 353 genes (Boyer et al. 2005). About half of POU5F1 targets also bind SOX2 and about 90% of these also bind NANOG (Boyer et al. 2005). Upon binding the transcription factors activate expression of one subset of target genes and repress another subset (Kim et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007). The targets listed in this module are those that have been described as composing activated genes in the core transcriptional network of pluripotent stem cells (Assou et al. 2007, Chavez et al. 2009, Jung et al. 2010). Inferences from mouse to human have been made with caution because of significant differences between the two species (Ginis et al. 2004).
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Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD, Garrigues J, Radke S, Todaro GJ, Salomon DS.; ''Differential expression of epidermal growth factor-related proteins in human colorectal tumors.''; PubMedEurope PMCScholia
Yang J, Gao C, Chai L, Ma Y.; ''A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells.''; PubMedEurope PMCScholia
Schuringa JJ, van der Schaaf S, Vellenga E, Eggen BJ, Kruijer W.; ''LIF-induced STAT3 signaling in murine versus human embryonal carcinoma (EC) cells.''; PubMedEurope PMCScholia
Chai L, Yang J, Di C, Cui W, Kawakami K, Lai R, Ma Y.; ''Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development.''; PubMedEurope PMCScholia
Matoba R, Niwa H, Masui S, Ohtsuka S, Carter MG, Sharov AA, Ko MS.; ''Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling.''; PubMedEurope PMCScholia
Babaie Y, Herwig R, Greber B, Brink TC, Wruck W, Groth D, Lehrach H, Burdon T, Adjaye J.; ''Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells.''; PubMedEurope PMCScholia
Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S.; ''Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan.''; PubMedEurope PMCScholia
Zhong Z, Wen Z, Darnell JE.; ''Stat3 and Stat4: members of the family of signal transducers and activators of transcription.''; PubMedEurope PMCScholia
Gebbia M, Ferrero GB, Pilia G, Bassi MT, Aylsworth A, Penman-Splitt M, Bird LM, Bamforth JS, Burn J, Schlessinger D, Nelson DL, Casey B.; ''X-linked situs abnormalities result from mutations in ZIC3.''; PubMedEurope PMCScholia
Kunarso G, Chia NY, Jeyakani J, Hwang C, Lu X, Chan YS, Ng HH, Bourque G.; ''Transposable elements have rewired the core regulatory network of human embryonic stem cells.''; PubMedEurope PMCScholia
Fong H, Hohenstein KA, Donovan PJ.; ''Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells.''; PubMedEurope PMCScholia
Ware SM, Peng J, Zhu L, Fernbach S, Colicos S, Casey B, Towbin J, Belmont JW.; ''Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects.''; PubMedEurope PMCScholia
Hentschke M, Kurth I, Borgmeyer U, Hübner CA.; ''Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3.''; PubMedEurope PMCScholia
Chandler LA, Sosnowski BA, Greenlees L, Aukerman SL, Baird A, Pierce GF.; ''Prevalent expression of fibroblast growth factor (FGF) receptors and FGF2 in human tumor cell lines.''; PubMedEurope PMCScholia
Bianco C, Rangel MC, Castro NP, Nagaoka T, Rollman K, Gonzales M, Salomon DS.; ''Role of Cripto-1 in stem cell maintenance and malignant progression.''; PubMedEurope PMCScholia
Lim LS, Hong FH, Kunarso G, Stanton LW.; ''The pluripotency regulator Zic3 is a direct activator of the Nanog promoter in ESCs.''; PubMedEurope PMCScholia
Drummond IA, Mukhopadhyay D, Sukhatme VP.; ''Expression of fetal kidney growth factors in a kidney tumor line: role of FGF2 in kidney development.''; PubMedEurope PMCScholia
de Castro NP, Rangel MC, Nagaoka T, Salomon DS, Bianco C.; ''Cripto-1: an embryonic gene that promotes tumorigenesis.''; PubMedEurope PMCScholia
Assou S, Le Carrour T, Tondeur S, Ström S, Gabelle A, Marty S, Nadal L, Pantesco V, Réme T, Hugnot JP, Gasca S, Hovatta O, Hamamah S, Klein B, De Vos J.; ''A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas.''; PubMedEurope PMCScholia
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR.; ''Human DNA methylomes at base resolution show widespread epigenomic differences.''; PubMedEurope PMCScholia
Ware SM, Harutyunyan KG, Belmont JW.; ''Zic3 is critical for early embryonic patterning during gastrulation.''; PubMedEurope PMCScholia
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R.; ''In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.''; PubMedEurope PMCScholia
Assou S, Cerecedo D, Tondeur S, Pantesco V, Hovatta O, Klein B, Hamamah S, De Vos J.; ''A gene expression signature shared by human mature oocytes and embryonic stem cells.''; PubMedEurope PMCScholia
Hughes SE, Hall PA.; ''Immunolocalization of fibroblast growth factor receptor 1 and its ligands in human tissues.''; PubMedEurope PMCScholia
Lim LS, Loh YH, Zhang W, Li Y, Chen X, Wang Y, Bakre M, Ng HH, Stanton LW.; ''Zic3 is required for maintenance of pluripotency in embryonic stem cells.''; PubMedEurope PMCScholia
Göke J, Jung M, Behrens S, Chavez L, O'Keeffe S, Timmermann B, Lehrach H, Adjaye J, Vingron M.; ''Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development.''; PubMedEurope PMCScholia
Arduini BL, Brivanlou AH.; ''Modulation of FOXD3 activity in human embryonic stem cells directs pluripotency and paraxial mesoderm fates.''; PubMedEurope PMCScholia
Eiselleova L, Matulka K, Kriz V, Kunova M, Schmidtova Z, Neradil J, Tichy B, Dvorakova D, Pospisilova S, Hampl A, Dvorak P.; ''A complex role for FGF-2 in self-renewal, survival, and adhesion of human embryonic stem cells.''; PubMedEurope PMCScholia
Liu Y, Labosky PA.; ''Regulation of embryonic stem cell self-renewal and pluripotency by Foxd3.''; PubMedEurope PMCScholia
Humphrey RK, Beattie GM, Lopez AD, Bucay N, King CC, Firpo MT, Rose-John S, Hayek A.; ''Maintenance of pluripotency in human embryonic stem cells is STAT3 independent.''; PubMedEurope PMCScholia
Player A, Wang Y, Bhattacharya B, Rao M, Puri RK, Kawasaki ES.; ''Comparisons between transcriptional regulation and RNA expression in human embryonic stem cell lines.''; PubMedEurope PMCScholia
Dvorak P, Dvorakova D, Koskova S, Vodinska M, Najvirtova M, Krekac D, Hampl A.; ''Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells.''; PubMedEurope PMCScholia
International Stem Cell Initiative, Adewumi O, Aflatoonian B, Ahrlund-Richter L, Amit M, Andrews PW, Beighton G, Bello PA, Benvenisty N, Berry LS, Bevan S, Blum B, Brooking J, Chen KG, Choo AB, Churchill GA, Corbel M, Damjanov I, Draper JS, Dvorak P, Emanuelsson K, Fleck RA, Ford A, Gertow K, Gertsenstein M, Gokhale PJ, Hamilton RS, Hampl A, Healy LE, Hovatta O, Hyllner J, Imreh MP, Itskovitz-Eldor J, Jackson J, Johnson JL, Jones M, Kee K, King BL, Knowles BB, Lako M, Lebrin F, Mallon BS, Manning D, Mayshar Y, McKay RD, Michalska AE, Mikkola M, Mileikovsky M, Minger SL, Moore HD, Mummery CL, Nagy A, Nakatsuji N, O'Brien CM, Oh SK, Olsson C, Otonkoski T, Park KY, Passier R, Patel H, Patel M, Pedersen R, Pera MF, Piekarczyk MS, Pera RA, Reubinoff BE, Robins AJ, Rossant J, Rugg-Gunn P, Schulz TC, Semb H, Sherrer ES, Siemen H, Stacey GN, Stojkovic M, Suemori H, Szatkiewicz J, Turetsky T, Tuuri T, van den Brink S, Vintersten K, Vuoristo S, Ward D, Weaver TA, Young LA, Zhang W.; ''Characterization of human embryonic stem cell lines by the International Stem Cell Initiative.''; PubMedEurope PMCScholia
Netzer C, Rieger L, Brero A, Zhang CD, Hinzke M, Kohlhase J, Bohlander SK.; ''SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin.''; PubMedEurope PMCScholia
Ma Y, Chai L, Cortez SC, Stopa EG, Steinhoff MM, Ford D, Morgan J, Maizel AL.; ''SALL1 expression in the human pituitary-adrenal/gonadal axis.''; PubMedEurope PMCScholia
Hafner C, Becker B, Landthaler M, Vogt T.; ''Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer.''; PubMedEurope PMCScholia
Son MY, Seol B, Han YM, Cho YS.; ''Comparative receptor tyrosine kinase profiling identifies a novel role for AXL in human stem cell pluripotency.''; PubMedEurope PMCScholia
Greber B, Lehrach H, Adjaye J.; ''Silencing of core transcription factors in human EC cells highlights the importance of autocrine FGF signaling for self-renewal.''; PubMedEurope PMCScholia
Lu J, Jeong HW, Kong N, Yang Y, Carroll J, Luo HR, Silberstein LE, Yupoma, Chai L.; ''Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex.''; PubMedEurope PMCScholia
Kim CG, Lee JJ, Jung DY, Jeon J, Heo HS, Kang HC, Shin JH, Cho YS, Cha KJ, Kim CG, Do BR, Kim KS, Kim HS.; ''Profiling of differentially expressed genes in human stem cells by cDNA microarray.''; PubMedEurope PMCScholia
Jin VX, O'Geen H, Iyengar S, Green R, Farnham PJ.; ''Identification of an OCT4 and SRY regulatory module using integrated computational and experimental genomics approaches.''; PubMedEurope PMCScholia
Tantin D, Gemberling M, Callister C, Fairbrother WG.; ''High-throughput biochemical analysis of in vivo location data reveals novel distinct classes of POU5F1(Oct4)/DNA complexes.''; PubMedEurope PMCScholia
Metsuyanim S, Harari-Steinberg O, Buzhor E, Omer D, Pode-Shakked N, Ben-Hur H, Halperin R, Schneider D, Dekel B.; ''Expression of stem cell markers in the human fetal kidney.''; PubMedEurope PMCScholia
Chakravarthy H, Boer B, Desler M, Mallanna SK, McKeithan TW, Rizzino A.; ''Identification of DPPA4 and other genes as putative Sox2:Oct-3/4 target genes using a combination of in silico analysis and transcription-based assays.''; PubMedEurope PMCScholia
Galán A, Montaner D, Póo ME, Valbuena D, Ruiz V, Aguilar C, Dopazo J, Simón C.; ''Functional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.''; PubMedEurope PMCScholia
Watanabe K, Meyer MJ, Strizzi L, Lee JM, Gonzales M, Bianco C, Nagaoka T, Farid SS, Margaryan N, Hendrix MJ, Vonderhaar BK, Salomon DS.; ''Cripto-1 is a cell surface marker for a tumorigenic, undifferentiated subpopulation in human embryonal carcinoma cells.''; PubMedEurope PMCScholia
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.; ''Core transcriptional regulatory circuitry in human embryonic stem cells.''; PubMedEurope PMCScholia
Dahéron L, Opitz SL, Zaehres H, Lensch MW, Andrews PW, Itskovitz-Eldor J, Daley GQ.; ''LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.''; PubMedEurope PMCScholia
Jung M, Peterson H, Chavez L, Kahlem P, Lehrach H, Vilo J, Adjaye J.; ''A data integration approach to mapping OCT4 gene regulatory networks operative in embryonic stem cells and embryonal carcinoma cells.''; PubMedEurope PMCScholia
Ginis I, Luo Y, Miura T, Thies S, Brandenberger R, Gerecht-Nir S, Amit M, Hoke A, Carpenter MK, Itskovitz-Eldor J, Rao MS.; ''Differences between human and mouse embryonic stem cells.''; PubMedEurope PMCScholia
The STAT3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Lister et al. 2009, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007) activate expression.
The FGF2 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009) and expression of the FGF2 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007).
The TDGF1 (CRIPTO) gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Tantin et al. 2008, Jung et al. 2010, Watanabe et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009, Watanabe et al. 2010). POU5F1 (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007, Watanabe et al. 2010) activate expression. Embryonal carcinoma cells that express higher levels of TDGF1 are more tumorigenic (Watanabe et al. 2010).
The FOXD3 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jung et al. 2010), SOX2 (Boyer et al. 2005, Lister et al. 2009), and NANOG (Boyer et al. 2005, Lister et al. 2009) and POU5F1 activates expression (Babaie et al. 2007, Kunarso et al. 2010).
The EPHA1 gene is bound by POU5F1 (OCT4) (Boyer et al. 2005, Jin et al. 2007, Jung et al. 2010, Kunarso et al. 2010, Goke et al. 2011), SOX2 (Boyer et al. 2005, Lister et al. 2009), NANOG (Boyer et al. 2005, Lister et al. 2009, Kunarso et al. 2010) and expression of the EPHA1 mRNA is activated by POU5F1 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007), and NANOG (Greber et al. 2007).
POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SALL1 gene (Boyer et al. 2005, Yang et al. 2010) and activate expression (Babaie et al. 2007). SALL4 binds the SALL1 promoter and represses expression thus making SALL4 and POU5F1 antagonistic (Yang et al. 2010).
POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene (Boyer et al. 2005, Lister et al. 2009) and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) activate expression. In mouse, Zic3 binds the Nanog promoter and activates transcription, thus forming a positive feedback loop (Lim et al. 2010).
The TDGF1 (CRIPTO) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. TDGF1/CRIPTO is expressed in embryonic stem cells (Adewumi et al. 2007, Li et al. 2006, Assou et al. 2009). GCNF (NR6A1) binds to the promoter of the TDGF1 (CRIPTO) gene and downregulates expression of TDGF1 (CRIPTO) during differentiation (Hentschke et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the TDGF1 gene and enhance transcription (Babaie et al. 2007, Greber et al. 2007, Watanabe et al. 2010). SOX2 binds the TDGF1 promoter adjacent to POU5F1 (Boyer et al. 2005). TDGF1 is a marker of undifferentiated stem cells (reviewed in Bianco et al. 2010, de Castro et al. 2010). Expression of TDGF1 is associated with tumorigenesis (Ciardiello et al. 1991).
The STAT3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. STAT3 is expressed in embryonic stem cells (Schuringa et al. 2002, Fong et al. 2008). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the STAT3 gene and enhance transcription (Boyer et al. 2005, Greber et al. 2007, Fong et al. 2008). The binding site of POU5F1 is adjacent to the binding site of SOX2 in the STAT3 promoter (Boyer et al. 2005). Signaling by LIF via STAT3 in murine but not human stem cells is sufficient to prevent differentiation (Schuringa et al. 2002, Humphrey et al. 2004, Daheron et al. 2004).
DPPA4 is expressed in pluripotent stem cells. The promoter of the DPPA4 gene binds OCT4 (POU5F1), SOX2, and NANOG (Player et al. 2006, Boyer et al. 2007, inferred from mouse homologs in Chakravarthy et al. 2008). OCT4 Knockdown experiments show OCT4 enhances expression of DPPA4 (Babaie et al. 2007).
The Forkhead box protein D3 (FOXD3) gene is transcribed and translated to yield FOXD3 protein. FOXD3 is expressed in blastomeres of the inner cell mass (Galan et al. 2010, Arduini et al. 2012). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FOXD3 gene and POU5F1 enhances transcription (Babaie et al. 2007, Kunarso et al. 2010). The binding site of POU5F1 is not adjacent to the binding site of SOX2 on the FOXD3 promoter (Boyer et al. 2005). FOXD3 is a molecular marker of stem cells (Calloni et al.2013) and a balance of FOXD3 expression is required to maintain pluripotency (Arduini and Brinvalou 2012, inferred from mouse in Liu and Labosky 2008).
The SALL1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SALL1 mRNA and protein are expressed in pituitary, adrenal cortex and the placenta in addition to kidney, testicular, and ovarian cells (Ma et al 2002, Chai et al. 2006). Mutations in SALL1 cause Townes-Brocks syndrome. The protein localizes to pericentric heterochromatin (Netzer et al. 2001). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SALL1 gene and enhance transcription (Boyer et al. 2005, Fong et al. 2008). SOX2 binds a site in the SALL1 promoter adjacent to the site bound by POU5F1 (Boyer et al. 2005). SALL4 binds the promoter of the SALL1 gene and represses transcription by associating with Mi-2 (NuRD) repressor complex (Lu et al. 2009, Yang et al. 2010).
The ZIC3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the ZIC3 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhances transcription. SOX2 binds adjacent to POU5F1 on the ZIC3 promoter (Boyer et al. 2005). ZIC3 is expressed in embryonic stem cells where it maintains pluripotency (Lim et al. 2007). As inferred from mouse, ZIC3 is involved in correct patterning during gastrulation (Ware et al. 2006) and mutations in ZIC3 cause heterotaxy in humans (Gebbia et al. 1997, Ware et al. 2004).
The EPHA1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EPHA1 is expressed most highly in epidermis of skin and is downregulated in nonmelanomal skin cancers (Hafner et al. 2006). EPHA1 is expressed at lower levels in liver, colon, small intestine, bladder, kidney, prostate, and thymus (Hafner et al. 2006). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the EPHA1 gene and OCT4 (Babaie et al. 2007, Greber et al. 2007, Kunarso et al. 2010), SOX2 (Greber et al. 2007) and NANOG (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the promoter of EPHA1 (Boyer et al. 2005). Expression and kinase activity of EPHA1 correlate with maintenance of pluripotency (Son et al. 2013).
The FGF2 (bFGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. FGF2 is expressed in most tissues including kidney, skin, liver, ureter, and vasculature (Hughes and Hall 1993). FGF2 is expressed in about 35% of tumor lines (Chandler et al. 1999). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the FGF2 gene and POU5F1 (Babaie et al. 2007, Greber et al. 2007) and SOX2 (Greber et al. 2007) enhance transcription. The binding site of POU5F1 is adjacent to the binding site of SOX2 on the FGF2 promoter (Boyer et al. 2005). FGF2 maintains human embryonic stem cells in an undifferentiated state (Dvorak et al. 2005, Eiselleova et al. 2009).
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