Oct-4

POU class 5 homeobox 1
Identifiers
Symbols	POU5F1 ; OCT3; OCT4; OTF-3; OTF3; OTF4; Oct-3; Oct-4
External IDs	OMIM: 164177 MGI: 101893 HomoloGene: 8422 GeneCards: POU5F1 Gene
Gene ontology Molecular function • transcription regulatory region sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • transcription factor binding • ubiquitin protein ligase binding • miRNA binding • sequence-specific DNA binding • transcription regulatory region DNA binding • poly(A) RNA binding Cellular component • nucleus • nucleoplasm • transcription factor complex • cytoplasm • cytosol Biological process • negative regulation of transcription from RNA polymerase II promoter • endodermal cell fate specification • blastocyst development • BMP signaling pathway involved in heart induction • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • response to wounding • anatomical structure morphogenesis • regulation of asymmetric cell division • regulation of gene expression • somatic stem cell maintenance • positive regulation of catenin import into nucleus • mRNA transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • positive regulation of SMAD protein import into nucleus • cell fate commitment involved in formation of primary germ layer • cardiac cell fate determination • negative regulation of gene silencing by miRNA • regulation of heart induction by regulation of canonical Wnt signaling pathway • regulation of methylation-dependent chromatin silencing Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5460	18999
Ensembl	ENSG00000204531	ENSMUSG00000024406
UniProt	Q01860	P20263
RefSeq (mRNA)	NM_001173531	NM_001252452
RefSeq (protein)	NP_001167002	NP_001239381
Location (UCSC)	Chr 6: 31.16 – 31.18 Mb	Chr 17: 35.51 – 35.51 Mb
PubMed search

Oct-4 (octamer-binding transcription factor 4) also known as POU5F1 (POU domain, class 5, transcription factor 1) is a protein that in humans is encoded by the POU5F1 gene.^[1] Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells.^[2] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.^[3]

The octamer (made of eight units) in this family of transcription factors is the DNA nucleotide sequence "ATTTGCAT", the etymology for the naming of the octamer transcription factor.^[4]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte but remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.^[5] Gene knockdown of Oct-4 promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.^[6] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.^[7]

Mouse embryos that are Oct-4-deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs

Orthologs of Oct-4 exist in humans and several other species including:

Species	Entrez GeneID	Chromosome	Location	RefSeq (mRNA)	RefSeq (protein)
Mus musculus	18999	17,17 B1; 17 19.23 cM	NC_000083.4, 35114104..35118822 (Plus Strand)	NM_013633.1	NP_038661.1
Homo sapiens	5460	6, 6p21.31	NC_000006.10, 31246432-31240107 (Minus Strand)	NM_002701.3	NP_002692.2 (full length isoform) NP_002692.1 (N-terminal truncated isoform)
Rattus norvegicus	294562	20	NW_001084776, 650467-655015 (Minus strand)	NM_001009178	NP_001009178
Danio rerio (Zebrafish)	303333	21	NC_007127.1, 27995548-28000317 (Minus strand)	NM_131112	NP_571187

Structural Information

Oct-4 contains the following protein domains:

Domain	Description	Length (AA)
POU domain	Found in Pit-Oct-Unc transcription factors	75
Homeodomain	DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner.	59

Implications in disease

Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.^[8]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem (ES) cells to determine requirements for Oct-4 in the maintenance of developmental potency.^[3] Although transcriptional determination has usually been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. A less-than-2-fold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down regulation induces divergent developmental programs. Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.

The transcription factors Oct-4, Sox2 and Nanog are capable of inducing the expression of each other, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, as well as in embryonic stem cells (which are cell lines derived from the inner cell mass).^[7]

Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse,^[9][10][11] demonstrating its capacity to induce an embryonic stem cell-like state. It was later deterimined that only two of these four factors, Oct4 and Klf4 were sufficient to reprogram mouse adult neural stem cells.^[12] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.^[13]

In embryonic stem cells

In in-vitro experiments of murine Embryonic Stem Cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.

Oct3/4 can both repress and activate the Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.^[14] However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1.^[14] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

In adult stem cells

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.).^[15] Other scientists have produced evidence to the contrary,^[16] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,^[17] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.^[18] Oct-4 has also been implicated as a marker of cancer stem cells.^[19][20]

See also

• Enhancer
• Histone
• Nanog (transcription factor)
• Pribnow box
• RNA polymerase
• Transcription factors
• Gene regulatory network
• Induced pluripotent stem cells (iPS) Cells

References

1. Takeda J, Seino S, Bell GI (Sep 1992). "Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues". Nucleic Acids Research 20 (17): 4613–20. doi:10.1093/nar/20.17.4613. PMC 334192. PMID 1408763.
2. Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells at MIT
3. Niwa H, Miyazaki J, Smith AG (Apr 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nature Genetics 24 (4): 372–6. doi:10.1038/74199. PMID 10742100.
4. Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB (Feb 1990). "Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution". Proceedings of the National Academy of Sciences of the United States of America 87 (3): 1099–103. doi:10.1073/pnas.87.3.1099. PMC 53418. PMID 1967834.
5. Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research 63 (9): 2244–50. PMID 12727846.
6. Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (Mar 2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924.
7. Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (Jul 2005). "Transcriptional regulation of nanog by OCT4 and SOX2". The Journal of Biological Chemistry 280 (26): 24731–7. doi:10.1074/jbc.M502573200. PMID 15860457.
8. Hochedlinger K, Yamada Y, Beard C, Jaenisch R (May 2005). "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell 121 (3): 465–77. doi:10.1016/j.cell.2005.02.018. PMID 15882627.
9. Okita K, Ichisaka T, Yamanaka S (Jul 2007). "Generation of germline-competent induced pluripotent stem cells". Nature 448 (7151): 313–7. doi:10.1038/nature05934. PMID 17554338.
10. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (Jul 2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature 448 (7151): 318–24. doi:10.1038/nature05944. PMID 17554336.
11. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (Jun 2007). "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution". Cell Stem Cell 1 (1): 55–70. doi:10.1016/j.stem.2007.05.014. PMID 18371336.
12. Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR (Jul 2008). "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature 454 (7204): 646–50. doi:10.1038/nature07061. PMID 18594515.
13. Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR (Feb 2009). "Oct4-induced pluripotency in adult neural stem cells". Cell 136 (3): 411–9. doi:10.1016/j.cell.2009.01.023. PMID 19203577.
14. Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y (Apr 1998). "Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site". Molecular and Cellular Biology 18 (4): 1866–78. PMC 121416. PMID 9528758.
15. For example:
    • Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE (Feb 2005). "Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis". Carcinogenesis 26 (2): 495–502. doi:10.1093/carcin/bgh321. PMID 15513931.
    • Kim JH, Jee MK, Lee SY, Han TH, Kim BS, Kang KS, Kang SK (2009). Mei L, ed. "Regulation of adipose tissue stromal cells behaviors by endogenic Oct4 expression control". PLOS ONE 4 (9): e7166. doi:10.1371/journal.pone.0007166. PMC 2747014. PMID 19777066.
16. Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, Jaenisch R (Oct 2007). "Oct4 expression is not required for mouse somatic stem cell self-renewal". Cell Stem Cell 1 (4): 403–15. doi:10.1016/j.stem.2007.07.020. PMC 2151746. PMID 18159219.
17. Lengner CJ, Welstead GG, Jaenisch R (Mar 2008). "The pluripotency regulator Oct4: a role in somatic stem cells?". Cell Cycle 7 (6): 725–8. doi:10.4161/cc.7.6.5573. PMID 18239456.
18. Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P, Lazzari L (Jul 2007). "Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker". Stem Cells 25 (7): 1675–80. doi:10.1634/stemcells.2006-0611. PMID 17379765.
19. Kim RJ, Nam JS (Jun 2011). "OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer". Laboratory Animal Research 27 (2): 147–52. doi:10.5625/lar.2011.27.2.147. PMC 3145994. PMID 21826175.
20. Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR (Apr 2007). "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer. Journal International Du Cancer 120 (7): 1598–602. doi:10.1002/ijc.22508. PMID 17205510.

Further reading

• Lamoury FM, Croitoru-Lamoury J, Brew BJ (2006). "Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1". Cytotherapy 8 (3): 228–42. doi:10.1080/14653240600735875. PMID 16793732.
• Hough SR, Clements I, Welch PJ, Wiederholt KA (Jun 2006). "Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog". Stem Cells 24 (6): 1467–75. doi:10.1634/stemcells.2005-0475. PMID 16456133.
• Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y (Feb 2006). "G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis". Nature Cell Biology 8 (2): 188–94. doi:10.1038/ncb1353. PMID 16415856.
• 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 (Sep 2005). "Core transcriptional regulatory circuitry in human embryonic stem cells". Cell 122 (6): 947–56. doi:10.1016/j.cell.2005.08.020. PMC 3006442. PMID 16153702.
• Gerrard L, Zhao D, Clark AJ, Cui W (2005). "Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency". Stem Cells 23 (1): 124–33. doi:10.1634/stemcells.2004-0102. PMID 15625129.
• Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M (Aug 2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes & Development 17 (16): 2048–59. doi:10.1101/gad.269303. PMC 196258. PMID 12923055.
• Schoorlemmer J, Kruijer W (Dec 1991). "Octamer-dependent regulation of the kFGF gene in embryonal carcinoma and embryonic stem cells". Mechanisms of Development 36 (1-2): 75–86. doi:10.1016/0925-4773(91)90074-G. PMID 1723621.
• Wey E, Lyons GE, Schäfer BW (Mar 1994). "A human POU domain gene, mPOU, is expressed in developing brain and specific adult tissues". European Journal of Biochemistry / FEBS 220 (3): 753–62. doi:10.1111/j.1432-1033.1994.tb18676.x. PMID 7908264.
• Crouau-Roy B, Amadou C, Bouissou C, Clayton J, Vernet C, Ribouchon MT, Pontarotti P (May 1994). "Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping". Genomics 21 (1): 241–3. doi:10.1006/geno.1994.1249. PMID 8088794.
• Guillaudeux T, Mattei MG, Depetris D, Le Bouteiller P, Pontarotti P (1993). "In situ hybridization localizes the human OTF3 to chromosome 6p21.3-->p22 and OTF3L to 12p13". Cytogenetics and Cell Genetics 63 (4): 212–4. doi:10.1159/000133537. PMID 8500351.
• Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E (Oct 1995). "Expression of transcription regulating genes in human preimplantation embryos". Human Reproduction 10 (10): 2787–92. PMID 8567814.
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M (Sep 1996). "Generation and analysis of 280,000 human expressed sequence tags". Genome Research 6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID 8889549.
• Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG (Nov 1997). "The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors". The Journal of Biological Chemistry 272 (47): 29852–8. doi:10.1074/jbc.272.47.29852. PMID 9368058.
• Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A (Oct 1998). "Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4". Cell 95 (3): 379–91. doi:10.1016/S0092-8674(00)81769-9. PMID 9814708.
• Gonzalez MI, Robins DM (Mar 2001). "Oct-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of SRC-1". The Journal of Biological Chemistry 276 (9): 6420–8. doi:10.1074/jbc.M008689200. PMID 11096094.
• Butteroni C, De Felici M, Schöler HR, Pesce M (Dec 2000). "Phage display screening reveals an association between germline-specific transcription factor Oct-4 and multiple cellular proteins". Journal of Molecular Biology 304 (4): 529–40. doi:10.1006/jmbi.2000.4238. PMID 11099378.
• Ezashi T, Ghosh D, Roberts RM (Dec 2001). "Repression of Ets-2-induced transactivation of the tau interferon promoter by Oct-4". Molecular and Cellular Biology 21 (23): 7883–91. doi:10.1128/MCB.21.23.7883-7891.2001. PMC 99954. PMID 11689681.
• Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R (Mar 2002). "The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression". Proceedings of the National Academy of Sciences of the United States of America 99 (6): 3663–7. doi:10.1073/pnas.062041099. PMC 122580. PMID 11891324.
• Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research 63 (9): 2244–50. PMID 12727846.
• Wang P, Branch DR, Bali M, Schultz GA, Goss PE, Jin T (Oct 2003). "The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells". The Biochemical Journal 375 (Pt 1): 199–205. doi:10.1042/BJ20030579. PMC 1223663. PMID 12841847.
• Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M (Aug 2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes & Development 17 (16): 2048–59. doi:10.1101/gad.269303. PMC 196258. PMID 12923055.
• Rajpert-De Meyts E, Hanstein R, Jørgensen N, Graem N, Vogt PH, Skakkebaek NE (Jun 2004). "Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads". Human Reproduction 19 (6): 1338–44. doi:10.1093/humrep/deh265. PMID 15105401.
• Matin MM, Walsh JR, Gokhale PJ, Draper JS, Bahrami AR, Morton I, Moore HD, Andrews PW (2005). "Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells". Stem Cells 22 (5): 659–68. doi:10.1634/stemcells.22-5-659. PMID 15342930.
• Baal N, Reisinger K, Jahr H, Bohle RM, Liang O, Münstedt K, Rao CV, Preissner KT, Zygmunt MT (Oct 2004). "Expression of transcription factor Oct-4 and other embryonic genes in CD133 positive cells from human umbilical cord blood". Thrombosis and Haemostasis 92 (4): 767–75. doi:10.1160/TH04-02-0079. PMID 15467907.

External links

• Oct-4 Transcription Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook POU5F1
• Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4