Transcriptional regulation of pluripotent stem cells (Homo sapiens)

From WikiPathways

Revision as of 11:40, 1 November 2018 by ReactomeTeam (Talk | contribs)
(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)
Jump to: navigation, search
1, 2, 5, 8, 9, 14...23, 2610-12, 63, 6610, 11, 31, 44, 45, 606, 22, 27, 33, 37...112, 13, 16, 22, 29...3, 4, 8, 11, 19...46, 527, 19, 27, 33, 55...7, 19, 27, 28, 33...23, 2619, 30, 34, 39, 40, 52...cytosolnucleoplasmSMAD4 NANOG ZIC3POU5F1 POLR2H FOXP1-ESPOLR2G POLR2G POLR2E POU5F1:SOX2:NANOG:SOX2 genePOLR2F POLR2I SALL4:SALL4 genePOLR2I PBX1 SALL4 gene POLR2F POU5F1RNA Polymerase IIholoenzyme complex(generic)POLR2C KLF4 POLR2D POU5F1 (OCT4), SOX2,NANOG activategenes related toproliferationPOLR2F POLR2A POLR2L POU5F1 gene POU5F1:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG genePOLR2K NANOG geneSALL4 NANOG POLR2J POLR2H POLR2H SOX2 POLR2J NANOG gene POLR2G p-Y705-STAT3 dimerPOLR2K POLR2D RNA Polymerase IIholoenzyme complex(generic)POU5F1 mRNANR5A1POLR2I POLR2C p-S465,S467-SMAD2 SALL4 POLR2J POLR2D POLR2C POU5F1:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:POU5F1 geneRNA Polymerase IIholoenzyme complex(generic)SMAD4:p-SMAD2:p-SMAD2p-S465,S467-SMAD2 ZSCAN10 POU5F1 NANOG SOX2 SOX2EPAS1HIF3AFOXP1-ES POLR2C POU5F1:STAT3:SALL4genePOLR2D p-Y705-STAT3 RNA Polymerase IIholoenzyme complex(generic)POLR2E SALL4 genePOLR2G POLR2E POLR2E PRDM14 POLR2H POLR2B POLR2I KLF4POLR2L POU5F1 NANOGSOX2 POLR2G POLR2J POLR2K SOX2 gene POLR2F SMAD4 p-S465,S467-SMAD2 SOX2 genePOLR2F POLR2A POLR2D POU5F1 POLR2L EPAS1 genePOLR2J POLR2B POLR2K POLR2B RNA Polymerase IIholoenzyme complex(generic)SMAD4 LIN28:POU5F1 mRNAPOLR2C POLR2B POLR2E POLR2A SALL4 gene LIN28APOLR2L POLR2H POU5F1 mRNA SALL4FOXP1-ES POLR2L LIN28A POLR2A PRDM14POU5F1 genep-Y705-STAT3 POLR2B POU5F1 (OCT4), SOX2,NANOG repress genesrelated todifferentiationPBX1POLR2I ZSCAN10POLR2A POLR2K 7, 11, 19, 28, 55...2, 9, 24, 33, 40...262, 9, 24, 33, 40...7, 19, 55, 63, 686, 49, 55, 58, 61...1110, 11


Description

Pluripotent stem cells are undifferentiated cells posessing an abbreviated cell cycle (reviewed in Stein et al. 2012), a characteristic profile of gene expression (Rao et al. 2004, Kim et al. 2006, Player et al. 2006, Wang et al 2006 using mouse, International Stem Cell Initiative 2007, Assou et al. 2007, Assou et al. 2009, Ding et al. 2012 using mouse), and the ability to self-renew and generate all cell types of the body except extraembryonic lineages (Marti et al. 2013, reviewed in Romeo et al. 2012). They are a major cell type in the inner cell mass of the early embryo in vivo, and cells with the same properties, induced pluripotent stem cells, can be generated in vitro from differentiated adult cells by overexpression of a set of transcription factor genes (Takahashi and Yamanaka 2006, Takahashi et al. 2007, Yu et al. 2007, Jaenisch and Young 2008, Stein et al. 2012, reviewed in Dejosez and Zwaka 2012).
Pluripotency is maintained by a self-reinforcing loop of transcription factors (Boyer et al. 2005, Rao et al. 2006, Matoba et al. 2006, Player et al. 2006, Babaie et al. 2007, Sun et al. 2008, Assou et al. 2009, reviewed in Kashyap et al. 2009, reviewed in Dejosez and Zwaka 2012). In vivo, initiation of pluripotency may depend on maternal factors transmitted through the oocyte (Assou et al. 2009) and on DNA demethylation in the zygote (recently reviewed in Seisenberger et al. 2013) and hypoxia experienced by the blastocyst in the reproductive tract before implantation (Forristal et al. 2010, reviewed in Mohyeldin et al. 2010). In vitro, induced pluripotency may initiate with demethylation and activation of the promoters of POU5F1 (OCT4) and NANOG (Bhutani et al. 2010). Hypoxia also significantly enhances conversion to pluripotent stem cells (Yoshida et al. 2009). POU5F1 and NANOG, together with SOX2, encode central factors in pluripotency and activate their own transcription (Boyer et al 2005, Babaie et al. 2007, Yu et al. 2007, Takahashi et al. 2007). The autoactivation loop maintains expression of POU5F1, NANOG, and SOX2 at high levels in stem cells and, in turn, complexes containing various combinations of these factors (Remenyi et al. 2003, Lam et al. 2012) activate the expression of a group of genes whose products are associated with rapid cell proliferation and repress the expression of a group of genes whose products are associated with cell differentiation (Boyer et al. 2005, Matoba et al. 2006, Babaie et al. 2007, Chavez et al. 2009, Forristal et al. 2010, Guenther 2011).
Comparisons between human and mouse embryonic stem cells must be made with caution and for this reason inferences from mouse have been used sparingly in this module. Human ESCs more closely resemble mouse epiblast stem cells in having inactivated X chromosomes, flattened morphology, and intolerance to passaging as single cells (Hanna et al. 2010). Molecularly, human ESCs differ from mouse ESCs in being maintained by FGF and Activin/Nodal/TGFbeta signaling rather than by LIF and canonical Wnt signaling (Greber et al. 2010, reviewed in Katoh 2011). In human ESCs POU5F1 binds and directly activates the FGF2 gene, however Pou5f1 does not activate Fgf2 in mouse ESCs (reviewed in De Los Angeles et al. 2012). Differences in expression patterns of KLF2, KLF4, KLF5, ESRRB, FOXD3, SOCS3, LIN28, NODAL were observed between human and mouse ESCs (Cai et al. 2010) as were differences in expression of EOMES, ARNT and several other genes (Ginis et al.2004). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 452723
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Katoh M.; ''Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells.''; PubMed Europe PMC
  2. 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.''; PubMed Europe PMC
  3. Matin MM, Walsh JR, Gokhale PJ, Draper JS, Bahrami AR, Morton I, Moore HD, Andrews PW.; ''Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells.''; PubMed Europe PMC
  4. Wang ZX, Kueh JL, Teh CH, Rossbach M, Lim L, Li P, Wong KY, Lufkin T, Robson P, Stanton LW.; ''Zfp206 is a transcription factor that controls pluripotency of embryonic stem cells.''; PubMed Europe PMC
  5. Romeo F, Costanzo F, Agostini M.; ''Embryonic stem cells and inducible pluripotent stem cells: two faces of the same coin?''; PubMed Europe PMC
  6. Chan KK, Zhang J, Chia NY, Chan YS, Sim HS, Tan KS, Oh SK, Ng HH, Choo AB.; ''KLF4 and PBX1 directly regulate NANOG expression in human embryonic stem cells.''; PubMed Europe PMC
  7. 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.''; PubMed Europe PMC
  8. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA.; ''Induced pluripotent stem cell lines derived from human somatic cells.''; PubMed Europe PMC
  9. 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.''; PubMed Europe PMC
  10. Bard JD, Gelebart P, Amin HM, Young LC, Ma Y, Lai R.; ''Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4.''; PubMed Europe PMC
  11. Yang J, Gao C, Chai L, Ma Y.; ''A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells.''; PubMed Europe PMC
  12. 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.''; PubMed Europe PMC
  13. Faddah DA, Wang H, Cheng AW, Katz Y, Buganim Y, Jaenisch R.; ''Single-cell analysis reveals that expression of nanog is biallelic and equally variable as that of other pluripotency factors in mouse ESCs.''; PubMed Europe PMC
  14. Greber B, Wu G, Bernemann C, Joo JY, Han DW, Ko K, Tapia N, Sabour D, Sterneckert J, Tesar P, Schöler HR.; ''Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells.''; PubMed Europe PMC
  15. Dejosez M, Zwaka TP.; ''Pluripotency and nuclear reprogramming.''; PubMed Europe PMC
  16. Filipczyk A, Gkatzis K, Fu J, Hoppe PS, Lickert H, Anastassiadis K, Schroeder T.; ''Biallelic expression of nanog protein in mouse embryonic stem cells.''; PubMed Europe PMC
  17. Sun Y, Li H, Liu Y, Mattson MP, Rao MS, Zhan M.; ''Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiation.''; PubMed Europe PMC
  18. Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH.; ''A protein interaction network for pluripotency of embryonic stem cells.''; PubMed Europe PMC
  19. Chew JL, Loh YH, Zhang W, Chen X, Tam WL, Yeap LS, Li P, Ang YS, Lim B, Robson P, Ng HH.; ''Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells.''; PubMed Europe PMC
  20. Gerrard L, Zhao D, Clark AJ, Cui W.; ''Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency.''; PubMed Europe PMC
  21. De Los Angeles A, Loh YH, Tesar PJ, Daley GQ.; ''Accessing naïve human pluripotency.''; PubMed Europe PMC
  22. Vallier L, Touboul T, Brown S, Cho C, Bilican B, Alexander M, Cedervall J, Chandran S, Ahrlund-Richter L, Weber A, Pedersen RA.; ''Signaling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells.''; PubMed Europe PMC
  23. Lei XX, Xu J, Ma W, Qiao C, Newman MA, Hammond SM, Huang Y.; ''Determinants of mRNA recognition and translation regulation by Lin28.''; PubMed Europe PMC
  24. 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.''; PubMed Europe PMC
  25. Cai J, Xie D, Fan Z, Chipperfield H, Marden J, Wong WH, Zhong S.; ''Modeling co-expression across species for complex traits: insights to the difference of human and mouse embryonic stem cells.''; PubMed Europe PMC
  26. Qiu C, Ma Y, Wang J, Peng S, Huang Y.; ''Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells.''; PubMed Europe PMC
  27. 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.''; PubMed Europe PMC
  28. Chia NY, Chan YS, Feng B, Lu X, Orlov YL, Moreau D, Kumar P, Yang L, Jiang J, Lau MS, Huss M, Soh BS, Kraus P, Li P, Lufkin T, Lim B, Clarke ND, Bard F, Ng HH.; ''A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity.''; PubMed Europe PMC
  29. Hyslop L, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S, Herbert M, Murdoch A, Strachan T, Lako M.; ''Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages.''; PubMed Europe PMC
  30. Rao RR, Calhoun JD, Qin X, Rekaya R, Clark JK, Stice SL.; ''Comparative transcriptional profiling of two human embryonic stem cell lines.''; PubMed Europe PMC
  31. Shih YR, Kuo TK, Yang AH, Lee OK, Lee CH.; ''Isolation and characterization of stem cells from the human parathyroid gland.''; PubMed Europe PMC
  32. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A.; ''Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.''; PubMed Europe PMC
  33. 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.''; PubMed Europe PMC
  34. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S.; ''Induction of pluripotent stem cells from adult human fibroblasts by defined factors.''; PubMed Europe PMC
  35. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE.; ''Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis.''; PubMed Europe PMC
  36. Lam CS, Mistri TK, Foo YH, Sudhaharan T, Gan HT, Rodda D, Lim LH, Chou C, Robson P, Wohland T, Ahmed S.; ''DNA-dependent Oct4-Sox2 interaction and diffusion properties characteristic of the pluripotent cell state revealed by fluorescence spectroscopy.''; PubMed Europe PMC
  37. 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.''; PubMed Europe PMC
  38. Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM.; ''Reprogramming towards pluripotency requires AID-dependent DNA demethylation.''; PubMed Europe PMC
  39. 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.''; PubMed Europe PMC
  40. 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.''; PubMed Europe PMC
  41. Martí M, Mulero L, Pardo C, Morera C, Carrió M, Laricchia-Robbio L, Esteban CR, Izpisua Belmonte JC.; ''Characterization of pluripotent stem cells.''; PubMed Europe PMC
  42. Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M.; ''Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers.''; PubMed Europe PMC
  43. 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.''; PubMed Europe PMC
  44. Rao S, Zhen S, Roumiantsev S, McDonald LT, Yuan GC, Orkin SH.; ''Differential roles of Sall4 isoforms in embryonic stem cell pluripotency.''; PubMed Europe PMC
  45. 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.''; PubMed Europe PMC
  46. Tian H, McKnight SL, Russell DW.; ''Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.''; PubMed Europe PMC
  47. 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.''; PubMed Europe PMC
  48. 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.''; PubMed Europe PMC
  49. Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H, Nakatsuji N, Tada T.; ''Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression.''; PubMed Europe PMC
  50. 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.''; PubMed Europe PMC
  51. Miyanari Y, Torres-Padilla ME.; ''Control of ground-state pluripotency by allelic regulation of Nanog.''; PubMed Europe PMC
  52. Forristal CE, Wright KL, Hanley NA, Oreffo RO, Houghton FD.; ''Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions.''; PubMed Europe PMC
  53. Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Persson JL, Gudas LJ, Mongan NP.; ''Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs.''; PubMed Europe PMC
  54. Hart AH, Hartley L, Ibrahim M, Robb L.; ''Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human.''; PubMed Europe PMC
  55. Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P.; ''Transcriptional regulation of nanog by OCT4 and SOX2.''; PubMed Europe PMC
  56. Cauffman G, Van de Velde H, Liebaers I, Van Steirteghem A.; ''Oct-4 mRNA and protein expression during human preimplantation development.''; PubMed Europe PMC
  57. Stein GS, Stein JL, van J Wijnen A, Lian JB, Montecino M, Medina R, Kapinas K, Ghule P, Grandy R, Zaidi SK, Becker KA.; ''The architectural organization of human stem cell cycle regulatory machinery.''; PubMed Europe PMC
  58. Navarro P, Festuccia N, Colby D, Gagliardi A, Mullin NP, Zhang W, Karwacki-Neisius V, Osorno R, Kelly D, Robertson M, Chambers I.; ''OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells.''; PubMed Europe PMC
  59. Ding J, Xu H, Faiola F, Ma'ayan A, Wang J.; ''Oct4 links multiple epigenetic pathways to the pluripotency network.''; PubMed Europe PMC
  60. Cauffman G, De Rycke M, Sermon K, Liebaers I, Van de Velde H.; ''Markers that define stemness in ESC are unable to identify the totipotent cells in human preimplantation embryos.''; PubMed Europe PMC
  61. Brown S, Teo A, Pauklin S, Hannan N, Cho CH, Lim B, Vardy L, Dunn NR, Trotter M, Pedersen R, Vallier L.; ''Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors.''; PubMed Europe PMC
  62. Hatano SY, Tada M, Kimura H, Yamaguchi S, Kono T, Nakano T, Suemori H, Nakatsuji N, Tada T.; ''Pluripotential competence of cells associated with Nanog activity.''; PubMed Europe PMC
  63. 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.''; PubMed Europe PMC
  64. Richards M, Tan SP, Tan JH, Chan WK, Bongso A.; ''The transcriptome profile of human embryonic stem cells as defined by SAGE.''; PubMed Europe PMC
  65. Fidalgo M, Faiola F, Pereira CF, Ding J, Saunders A, Gingold J, Schaniel C, Lemischka IR, Silva JC, Wang J.; ''Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming.''; PubMed Europe PMC
  66. 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.''; PubMed Europe PMC
  67. Guenther MG.; ''Transcriptional control of embryonic and induced pluripotent stem cells.''; PubMed Europe PMC
  68. 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.''; PubMed Europe PMC
  69. Seisenberger S, Peat JR, Hore TA, Santos F, Dean W, Reik W.; ''Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers.''; PubMed Europe PMC
  70. Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O'Hanlon D, Sung HK, Alvarez M, Talukder S, Pan Q, Mazzoni EO, Nedelec S, Wichterle H, Woltjen K, Hughes TR, Zandstra PW, Nagy A, Wrana JL, Blencowe BJ.; ''An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.''; PubMed Europe PMC
  71. 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.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
101537view11:40, 1 November 2018ReactomeTeamreactome version 66
101072view21:22, 31 October 2018ReactomeTeamreactome version 65
100602view19:57, 31 October 2018ReactomeTeamreactome version 64
100153view16:42, 31 October 2018ReactomeTeamreactome version 63
99703view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99286view12:46, 31 October 2018ReactomeTeamreactome version 62
94014view13:51, 16 August 2017ReactomeTeamreactome version 61
93633view11:29, 9 August 2017ReactomeTeamreactome version 61
88361view16:39, 1 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86746view09:25, 11 July 2016ReactomeTeamreactome version 56
83336view10:49, 18 November 2015ReactomeTeamVersion54
81491view13:01, 21 August 2015ReactomeTeamVersion53
76135view13:17, 11 June 2014AnweshaFixed random error in comment source
75706view11:05, 10 June 2014ReactomeTeamReactome 48 Update
75533view19:23, 9 June 2014MaintBotchanged description source
75513view12:25, 5 June 2014AnweshaNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
EPAS1 geneGeneProductENSG00000116016 (Ensembl)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
FOXP1-ES ProteinQ9H334-8 (Uniprot-TrEMBL)
FOXP1-ESProteinQ9H334-8 (Uniprot-TrEMBL)
HIF3AProteinQ9Y2N7 (Uniprot-TrEMBL)
KLF4 ProteinO43474 (Uniprot-TrEMBL)
KLF4ProteinO43474 (Uniprot-TrEMBL)
LIN28:POU5F1 mRNAComplexR-HSA-500373 (Reactome) LIN28 binds the R2 region of the POU5F1 (OCT4) mRNA and increases translation of a luciferase reporter mRNA containing the binding site (Qiu et al. 2009, Lei et al. 2012). Reduction of LIN28 levels in embryonic stem cells causes a reduction in POU5F1 protein (Qiu et al. 2009).
LIN28A ProteinQ9H9Z2 (Uniprot-TrEMBL)
LIN28AProteinQ9H9Z2 (Uniprot-TrEMBL)
NANOG ProteinQ9H9S0 (Uniprot-TrEMBL)
NANOG gene ProteinENSG00000111704 (Ensembl)
NANOG geneGeneProductENSG00000111704 (Ensembl)
NANOGProteinQ9H9S0 (Uniprot-TrEMBL)
NR5A1ProteinQ13285 (Uniprot-TrEMBL)
PBX1 ProteinP40424 (Uniprot-TrEMBL)
PBX1ProteinP40424 (Uniprot-TrEMBL)
POLR2A ProteinP24928 (Uniprot-TrEMBL)
POLR2B ProteinP30876 (Uniprot-TrEMBL)
POLR2C ProteinP19387 (Uniprot-TrEMBL)
POLR2D ProteinO15514 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2G ProteinP62487 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2I ProteinP36954 (Uniprot-TrEMBL)
POLR2J ProteinP52435 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
POU5F1 (OCT4), SOX2,

NANOG activate genes related to

proliferation
PathwayR-HSA-2892247 (Reactome) 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).
POU5F1 (OCT4), SOX2,

NANOG repress genes related to

differentiation
PathwayR-HSA-2892245 (Reactome) 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 in the core transcriptional network of pluripotent stem cells and repress another subset (Kim et al. 2006, Matoba et al. 2006, Player et al. 2006, Assou et al. 2007, Babaie et al. 2007, Chavez et al. 2009, Jung et al. 2010). The target genes listed in this module are the repressed genes. Caution must be used when making inferences about human stem cells from mouse stem cells because of significant differences between the two species (Ginis et al. 2004).
POU5F1 ProteinQ01860 (Uniprot-TrEMBL)
POU5F1 gene ProteinENSG00000204531 (Ensembl)
POU5F1 geneGeneProductENSG00000204531 (Ensembl)
POU5F1 mRNA ProteinENST00000259915 (Ensembl)
POU5F1 mRNARnaENST00000259915 (Ensembl)
POU5F1:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG geneComplexR-HSA-480463 (Reactome) KLF4, PBX1, OCT4 (POU5F1), SOX2, and NANOG bind the promoter of the NANOG gene.
POU5F1:SOX2:NANOG:SOX2 geneComplexR-HSA-480572 (Reactome)
POU5F1:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:POU5F1 geneComplexR-HSA-1112611 (Reactome)
POU5F1:STAT3:SALL4 geneComplexR-HSA-2889026 (Reactome)
POU5F1ProteinQ01860 (Uniprot-TrEMBL)
PRDM14 ProteinQ9GZV8 (Uniprot-TrEMBL)
PRDM14ProteinQ9GZV8 (Uniprot-TrEMBL)
RNA Polymerase II

holoenzyme complex

(generic)
ComplexR-HSA-209680 (Reactome)
SALL4 ProteinQ9UJQ4 (Uniprot-TrEMBL)
SALL4 gene ProteinENSG00000101115 (Ensembl)
SALL4 geneGeneProductENSG00000101115 (Ensembl)
SALL4:SALL4 geneComplexR-HSA-2889008 (Reactome)
SALL4ProteinQ9UJQ4 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4:p-SMAD2:p-SMAD2ComplexR-HSA-206827 (Reactome)
SOX2 ProteinP48431 (Uniprot-TrEMBL)
SOX2 gene ProteinENSG00000181449 (Ensembl)
SOX2 geneGeneProductENSG00000181449 (Ensembl)
SOX2ProteinP48431 (Uniprot-TrEMBL)
ZIC3ProteinO60481 (Uniprot-TrEMBL)
ZSCAN10 ProteinQ96SZ4 (Uniprot-TrEMBL)
ZSCAN10ProteinQ96SZ4 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3 dimerComplexR-HSA-1112525 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ArrowR-HSA-452894 (Reactome)
EPAS1 geneR-HSA-480301 (Reactome)
EPAS1ArrowR-HSA-452392 (Reactome)
EPAS1ArrowR-HSA-452838 (Reactome)
EPAS1ArrowR-HSA-452894 (Reactome)
EPAS1ArrowR-HSA-480301 (Reactome)
FOXP1-ESR-HSA-1112609 (Reactome)
FOXP1-ESR-HSA-480204 (Reactome)
HIF3AArrowR-HSA-480301 (Reactome)
KLF4R-HSA-480204 (Reactome)
LIN28:POU5F1 mRNAArrowR-HSA-2889036 (Reactome)
LIN28:POU5F1 mRNAArrowR-HSA-500366 (Reactome)
LIN28:POU5F1 mRNAR-HSA-2889036 (Reactome)
LIN28AR-HSA-500366 (Reactome)
NANOG geneR-HSA-452838 (Reactome)
NANOG geneR-HSA-480204 (Reactome)
NANOGArrowR-HSA-452838 (Reactome)
NANOGR-HSA-1112609 (Reactome)
NANOGR-HSA-480204 (Reactome)
NANOGR-HSA-480685 (Reactome)
NR5A1ArrowR-HSA-452392 (Reactome)
PBX1R-HSA-480204 (Reactome)
POU5F1 geneR-HSA-1112609 (Reactome)
POU5F1 geneR-HSA-452392 (Reactome)
POU5F1 mRNAArrowR-HSA-452392 (Reactome)
POU5F1 mRNAR-HSA-500366 (Reactome)
POU5F1:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG geneArrowR-HSA-452838 (Reactome)
POU5F1:SOX2:NANOG:KLF4:PBX1:SMAD2:FOXP1-ES:NANOG geneArrowR-HSA-480204 (Reactome)
POU5F1:SOX2:NANOG:SOX2 geneArrowR-HSA-480685 (Reactome)
POU5F1:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:POU5F1 geneArrowR-HSA-1112609 (Reactome)
POU5F1:SOX2:NANOG:ZSCAN10:PRDM14:SMAD2:SALL4:FOXP1-ES:POU5F1 geneArrowR-HSA-452392 (Reactome)
POU5F1:STAT3:SALL4 geneArrowR-HSA-2895778 (Reactome)
POU5F1:STAT3:SALL4 geneArrowR-HSA-480520 (Reactome)
POU5F1ArrowR-HSA-2889036 (Reactome)
POU5F1R-HSA-1112609 (Reactome)
POU5F1R-HSA-2895778 (Reactome)
POU5F1R-HSA-480204 (Reactome)
POU5F1R-HSA-480685 (Reactome)
PRDM14R-HSA-1112609 (Reactome)
R-HSA-1112609 (Reactome) POU5F1 (OCT4), SOX2, and NANOG bind distinct sites in the promoter of the POU5F1 gene (Boyer et al. 2005, Chew et al. 2005, Rodda et al. 2005, Jin et al. 2007, Lister et al. 2009, Jung et al. 2010, Goke et al. 2011). The set of target genes of POU5F1, SOX2, and NANOG includes POU5F1, SOX2, and NANOG themselves, thus their expression is a component of an autoregulatory loop . Activin/Nodal signaling also regulates POU5F1 transcription via SMAD2 and SMAD3 (Brown et al. 2011). PRDM14 binds the POU5F1 promoter and regulates transcription (Chia et al. 2010).
R-HSA-2889036 (Reactome) The POU5F1 (OCT4) mRNA is translated to yield protein. LIN28 bound to the mRNA appears to enhance translation (Qiu et al. 2009, Lei et al. 2012).
R-HSA-2895778 (Reactome) POU5F1 (OCT4) and STAT3 bind the promoter of the SALL4 gene and activate its transcription (Babaie et al. 2007, Tantin et al. 2008, Bard et al. 2009, Yang et al. 2010). SALL4, in turn, positively regulates POU5F1 expression (Yang et al. 2010). In mouse STAT3 is activated by Leukemia Inhibitory Factor (LIF), however LIF in humans does not have the same activity in promoting stem cell maintenance (Humphrey et al. 2004).
R-HSA-2972968 (Reactome) SALL4 binds the promoter of the SALL4 gene and represses its own expression (Yang et al. 2010).
R-HSA-452392 (Reactome) The POU5F1 (OCT4) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Rao et al. 2004, Richards et al. 2004, Cauffman et al. 2005, Tai et al. 2005, Gerrard et al. 2005, Li et al. 2006, Adewumi et al. 2007,Assou etal. 2007). POU5F1 mRNA and protein are found in the cytoplasm of oocytes and cleavage-stage embryos (Cauffman et al. 2005). POU5F1 protein becomes nuclear during compaction, and protein and mRNA are present in inner cell mass and trophectoderm (Cauffman et al. 2005). Transcripts are also detectable in some differentiated tissues (Cauffman et al. 2005). POU5F1 is expressed in adult stem cells and cancers (Tai et al. 2005). POU5F1, SOX2, NANOG, SALL4, and SF-1(NR5A1) bind the promoter of the POU5F1 gene and enhance transcription (Matin et al. 2004, Chew et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Greber et al. 2007, Wang et al. 2007, Yang et al. 2010, Chia et al. 2010). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA. SALL4 binds the promoter of the POU5F1 gene and activates transcription of POU5F1 (Yang et al. 2010). POU5F1 activates SALL4 expression thus forming a self-reinforcing loop. Activation-induced cytidine deaminase (AID) binds the methylated promoter of the POU5F1 gene, demethylates it, and enhances expression of POU5F1 (Bhutani et al. 2009). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to enhance expression of POU5F1 (Forristal et al. 2010). LIN28 binds the POU5F1 mRNA and increases translation (Qiu et al. 2009).
R-HSA-452838 (Reactome) The NANOG gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Chambers et al. 2003, Hart et al. 2004, Hatano et al. 2005, Hyslop et al. 2005, Li et al. 2006). NANOG protein is not detected in oocytes or early cleavage-stage embryos, but is seen later in some but not all nuclei of the inner cell mass of blastocysts (Cauffman et al. 2009). KLF4, PBX1, POU5F1 (OCT4), SOX2, NANOG, and SMAD2 bind the promoter of the NANOG gene and enhance transcription (Boyer et al. 2005, Rodda et al. 2005, Kuroda et al. 2005, Babaie et al. 2007, Assou et al. 2007, Greber et al. 2007, Vallier et al. 2009, Brown et al. 2011). Activation-induced cytidine deaminase (AID) binds the methylated NANOG promoter and demethylates it (Bhutani et al. 2009). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to enhance expression of NANOG (Forristal et al. 2010). In mouse Nanog negatively regulates its own expression and this may account for the heterogeneous expression observed in cells of the inner cell mass (Fidalgo et al. 2012, Navarro et al. 2012). In human embryonic stem cells NANOG has been observed to be expressed monoallelically in the early pre-implantation embryo then expression becomes biallelic (Miyanari and Torres-Padilla 2012), however this is controversial because expreiments in mouse embryonic stem cells have shown biallelic expression (Faddah et al. 2013, Filipczyk et al. 2013). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA. In mice KLF4 interacts with POU5F1 and SOX2.
R-HSA-452894 (Reactome) The SOX2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Rao et al. 2004, Richards et al. 2004). SOX2 protein is expressed in the cytoplasm of oocytes and day-2 cleavage-stage embryos and in the nuclei of all cells of the inner cell mass of blastocysts (Cauffman et al. 2009). POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the SOX2 gene and enhance transcription (Chew et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Assou et al. 2007, Greber et al. 2007). POU5F1 and SOX2 bind adjacent sites at the promoter and form a heterodimer on the DNA (Boyer et al. 2005). Hypoxia acts via HIF3A and EPAS1 (HIF2A) to activate expression of SOX2 (Forristal et al. 2010).
R-HSA-480204 (Reactome) KLF4, PBX1, POU5F1 (OCT4), SOX2, and NANOG bind the promoter of the NANOG gene and enhance expression of NANOG (Rodda et al. 2005, Boyer et al. 2005, Babaie et al. 2007, Jin et al. 2007, Chan et al. 2009, Vallier et al. 2009, Jung et al. 2011). In mouse Nanog has been shown to repress its own expression (Fidalgo et al. 2012, Navarro et al. 2012). ZIC3, a NANOG target, also positively regulates NANOG expression, possibly by binding the NANOG promoter and activating transcription (Lim et al. 2007). Activin/Nodal signaling regulates NANOG via SMAD2 and SMAD3 (Brown et al. 2011)
R-HSA-480301 (Reactome) The EPAS1 (HIF2A) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. EPAS1 is expressed in most adult tissues, but not in peripheral blood leukocytes (Tian et al. 1997). Normoxia causes constitutive oxygen-dependient hydroxylation of EPAS1 on asparagine and proline residues, resulting in degradation of EPAS1 via ubiquitinylation. Hypoxia therefore inhibits degradation of EPAS1 and also causes an increase in EPAS1 expression via HIF3A in embryonic stem cells, which experience hypoxic conditions in the reproductive tract prior to implantation (Forristal et al. 2010).
R-HSA-480520 (Reactome) The SALL4 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. SALL4 protein is expressed weakly in the nuclei and cytoplasm of oocytes and day-2 cleavage-stage embryos and is expressed strongly in nuclei of blastocysts (Cauffman et al. 2009) and in induced pluripotent stem cells (Nishino et al. 2010). POU5F1 (OCT4) and STAT3 bind the promoter of the SALL4 gene and enhance transcription (Yang et al. 2010, Bard et al. 2009). SALL4 activates expression of POU5F1, thus forming a self-reinforcing loop (Yang et al. 2010). SALL4 binds the promoter of the SALL4 gene and represses transcription, thus forming a negative autoregulatory loop (Yang et al. 2010). As inferred from mouse the shorter isoform of SALL4, SALL4B is more effective at maintaining pluripotency (Rao et al. 2010).
R-HSA-480685 (Reactome) POU5F1 (OCT4), SOX2, and NANOG bind distinct sites in the promoter of the SOX2 gene (Boyer et al. 2005, Jin et al. 2007, Lister et al. 2009, Jung et al. 2010). The set of target genes of POU5F1, SOX2, and NANOG includes POU5F1, SOX2, and NANOG themselves, thus their expression is a component of an autoregulatory loop (Boyer et al. 2005, Chew et al. 2005, Rodda et al. 2005, Babaie et al. 2007, Jung et al. 2010, Goke et al. 2011).
R-HSA-500366 (Reactome) LIN28 binds the R2 region of the POU5F1 (OCT4) mRNA and increases translation of a luciferase reporter mRNA containing the binding site (Qiu et al. 2009, Lei et al. 2012). Reduction of LIN28 levels in embryonic stem cells causes a reduction in POU5F1 protein (Qiu et al. 2009).
RNA Polymerase II

holoenzyme complex

(generic)
mim-catalysisR-HSA-452392 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
mim-catalysisR-HSA-452838 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
mim-catalysisR-HSA-452894 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
mim-catalysisR-HSA-480301 (Reactome)
RNA Polymerase II

holoenzyme complex

(generic)
mim-catalysisR-HSA-480520 (Reactome)
SALL4 geneR-HSA-2895778 (Reactome)
SALL4 geneR-HSA-2972968 (Reactome)
SALL4 geneR-HSA-480520 (Reactome)
SALL4:SALL4 geneArrowR-HSA-2972968 (Reactome)
SALL4:SALL4 geneTBarR-HSA-480520 (Reactome)
SALL4ArrowR-HSA-480520 (Reactome)
SALL4R-HSA-1112609 (Reactome)
SALL4R-HSA-2972968 (Reactome)
SMAD4:p-SMAD2:p-SMAD2R-HSA-1112609 (Reactome)
SMAD4:p-SMAD2:p-SMAD2R-HSA-480204 (Reactome)
SOX2 geneR-HSA-452894 (Reactome)
SOX2 geneR-HSA-480685 (Reactome)
SOX2ArrowR-HSA-452894 (Reactome)
SOX2R-HSA-1112609 (Reactome)
SOX2R-HSA-480204 (Reactome)
SOX2R-HSA-480685 (Reactome)
ZIC3ArrowR-HSA-452838 (Reactome)
ZSCAN10R-HSA-1112609 (Reactome)
p-Y705-STAT3 dimerR-HSA-2895778 (Reactome)
Personal tools