Oct-4

For the day, see October 4.

"Oct-3" redirects here. For the day, see October 3.

POU5F1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OCP, 3L1P
Identifiers
Aliases	POU5F1 , OCT3, OCT4, OTF-3, OTF3, OTF4, Oct-3, Oct-4, POU class 5 homeobox 1, Oct3/4
External IDs	OMIM: 164177; MGI: 101893; HomoloGene: 8422; GeneCards: POU5F1; OMA:POU5F1 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) [1] Band 6p21.33 Start 31,164,337 bp [1] End 31,180,731 bp [1]
Gene location (Mouse) Chr. Chromosome 17 (mouse) [2] Band 17 B1|17 18.69 cM Start 35,816,915 bp [2] End 35,821,669 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gonad right uterine tube endometrium human kidney body of pancreas body of stomach mucosa of transverse colon testicle left uterine tube fundus Top expressed in blastocyst epiblast embryo morula morula primordial germ cell zygote inner cell mass primitive streak ooblast More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding sequence-specific DNA binding miRNA binding DNA-binding transcription factor activity transcription factor binding transcription cis-regulatory region binding protein binding DNA-binding transcription repressor activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific ubiquitin protein ligase binding RNA binding Cellular component cytoplasm cytosol transcription regulator complex nucleoplasm nucleus mitochondrion Biological process regulation of transcription, DNA-templated somatic stem cell population maintenance negative regulation of gene silencing by miRNA cell fate commitment involved in formation of primary germ layer endodermal cell fate specification anatomical structure morphogenesis mRNA transcription by RNA polymerase II regulation of asymmetric cell division negative regulation of transcription by RNA polymerase II transcription by RNA polymerase II transcription, DNA-templated regulation of DNA methylation-dependent heterochromatin assembly multicellular organism development cardiac cell fate determination response to wounding BMP signaling pathway involved in heart induction regulation of gene expression regulation of heart induction by regulation of canonical Wnt signaling pathway blastocyst development positive regulation of transcription by RNA polymerase II positive regulation of SMAD protein signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5460 18999 Ensembl ENSG00000230336 ENSG00000206454 ENSG00000204531 ENSG00000237582 ENSG00000229094 ENSG00000233911 ENSG00000235068 ENSMUSG00000024406 UniProt Q01860 P20263 RefSeq (mRNA) NM_203289 NM_001173531 NM_001285986 NM_001285987 NM_002701 NM_001252452 NM_013633 RefSeq (protein) NP_001167002 NP_001272915 NP_001272916 NP_002692 NP_976034 NP_001272915.1 NP_001239381 NP_038661 Location (UCSC) Chr 6: 31.16 – 31.18 Mb Chr 17: 35.82 – 35.82 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^[5] Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. ^[6] 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. ^[7]

Octamer-binding transcription factor 4, OCT-4, is a transcription factor protein that is encoded by the POU5F1 gene and is part of the POU (Pit-Oct-Unc) family. ^[8] OCT-4 consists of an octamer motif, a particular DNA sequence of AGTCAAAT that binds to their target genes and activates or deactivates certain expressions. These gene expressions then lead to phenotypic changes in stem cell differentiation during the development of a mammalian embryo. ^[9] It plays a vital role in determining the fates of both inner mass cells and embryonic stem cells and has the ability to maintain pluripotency throughout embryonic development. ^[10] Recently, it has been noted that OCT-4 not only maintains pluripotency in embryonic cells but also has the ability to regulate cancer cell proliferation and can be found in various cancers such as pancreatic, lung, liver and testicular germ cell tumors in adult germ cells. ^[11] Another defect this gene can have is dysplastic growth in epithelial tissues which are caused by a lack of OCT-4 within the epithelial cells. ^[12]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors. ^[13] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal. ^[14] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together. ^[15]

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 in humans and other species include:

Species	Entrez GeneID	Chromosome	Location	RefSeq (mRNA)	RefSeq (protein)
Mus musculus (mouse)	18999	17,17 B1; 17 19.23 cM	NC_000083.4, 35114104..35118822 (Plus Strand)	NM_013633.1	NP_038661.1
Homo sapiens (human)	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 (rat)	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

Structure

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 homodimers 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. ^[16]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency. ^[7] Although transcriptional determination has often 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. An increase in expression of less than 2-fold 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. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation. ^[17] 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 part of a complex regulatory network, with Oct-4 and Sox2 being capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines ^[18] (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells. ^[15] While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed. ^[17]

Role in reprogramming

Oct-4 is one of the transcription factors that is used to create induced pluripotent stem cells (iPSCs), together with Sox2, Klf4, and often c-Myc (OSKM) in mice, ^{[19] [20] [21]} demonstrating its capacity to induce an embryonic stem-cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs via Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene. ^[22] It was later determined that only two of these four factors, namely Oct4 and Klf4, are sufficient to reprogram mouse adult neural stem cells. ^[23] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation. ^[24] Moreover, while Sox2, Klf4, and cMyc could be replaced by their respective family members, Oct4's closer relatives, Oct1 and Oct6, fail to induce pluripotency, thus demonstrating the exclusiveness of Oct4 among POU transcription factors. ^[25] However, later it was shown that Oct4 could be completely omitted from the Yamanaka cocktail, and the remaining three factors, Sox2, Klf4, and cMyc (SKM) could generate mouse iPSCs with dramatically enhanced developmental potential. ^[26] This suggests that Oct4 increases the efficiency of reprogramming, but decreases the quality of resulting iPSCs. This is possibly due to a mutated OCT4 DBD cysteine residue (Cys48) that has been identified as a central reprogramming determinant. ^[27] The serine residue in OCT1 is mutated in the presence of the OCT4 N terminus, which conversely causes OCT4's serine (converted from cysteine) to reduce reprogramming efficiency by 60%. ^[27]

In embryonic stem cells

• In in vitro experiments of mouse 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 promoter of Rex1 . In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1. ^[28] However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1. ^[28] 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.
• Oct4 contributes to the rapid cell cycle of ESCs by promoting progression through the G1 phase, specifically through transcriptional inhibition of cyclin-dependent kinase inhibitors such as p21. ^[29]
• CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation. ^[30]
• Oct3/4 represses Suv39h1 expression through the activation of an antisense long non-coding RNA. Suv39h1 inhibition maintains low level of H3K9me3 in pluripotent cells limiting the formation of heterochromatin. ^[31]

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.). ^[32] Other scientists have produced evidence to the contrary, ^[33] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal, ^[34] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression. ^[35] Oct-4 has also been implicated as a marker of cancer stem cells. ^{[36] [37]} A majority of Oct4 cancer stem-like cell studies (CSC) report a positive association between expression of OCT4 and chemoresistance. ^[38] Chemotherapy resulting in the enrichment of CSCs showed changes in the phenotypes and increased stem cell markers of OCT4. ^[39] Various cancers such as lung cancer, bladder cancer, and mesothelioma cells with high OCT4 expressions showed resistance to cisplatin, general drug resistance, and tumor recurrence. ^[38] Breast cancer patients had tamoxifen resistance and poor clinical outcomes associated with OCT4. ^[40] OCT4 knock-downs increase sensitivity to cisplatin and irradiation in lung cells, retained tumorigenicity in glioma-initiating cells, and metastasis mediation in ovarian cancer. ^[38] In in vitro studies looking at cisplatin, knock-down of OCT4 increased their sensitivity and reduced cell proliferation. ^[38] Further investigation is needed due to the sparsity of stem cells within tumors and their heterogeneity.

See also

• Enhancer
• Histone
• Pribnow box
• RNA polymerase
• Gene regulatory network

References

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27. Shen Z, Wu Y, Manna A, Yi C, Cairns BR, Evason KJ, et al. (May 2024). "Oct4 redox sensitivity potentiates reprogramming and differentiation". Genes & Development. 38 (7–8): 308–321. doi:10.1101/gad.351411.123. PMC   11146590 . PMID   38719541.
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36. Kim RJ, Nam JS (June 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.
37. Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR (April 2007). "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer. 120 (7): 1598–602. doi: 10.1002/ijc.22508 . PMID   17205510. S2CID   23516214.
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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 (June 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. S2CID   27609337.
• Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, et al. (February 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. S2CID   23740530.
• 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. S2CID   21603127.
• Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M (August 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 (December 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. S2CID   8353907.
• Wey E, Lyons GE, Schäfer BW (March 1994). "A human POU domain gene, mPOU, is expressed in developing brain and specific adult tissues". European Journal of Biochemistry. 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, et al. (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 (October 1995). "Expression of transcription regulating genes in human preimplantation embryos". Human Reproduction. 10 (10): 2787–92. doi:10.1093/oxfordjournals.humrep.a135792. PMID   8567814.
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External links

• Oct-4+Transcription+Factor at the U.S. 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 Archived 2008-04-09 at the Wayback Machine