Oct-4
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| Location (UCSC) | Chr 6: 31.16 – 31.18 Mb | Chr 17: 35.82 – 35.82 Mb | |||||||
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Oct-4 (
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
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
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.
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.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
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.
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 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
- CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.[29]
- 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. [30]
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.).[31] Other scientists have produced evidence to the contrary,[32] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[33] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[34] Oct-4 has also been implicated as a marker of cancer stem cells.[35][36]
See also
References
- ^ a b c ENSG00000206454, ENSG00000204531, ENSG00000237582, ENSG00000229094, ENSG00000233911, ENSG00000235068 GRCh38: Ensembl release 89: ENSG00000230336, ENSG00000206454, ENSG00000204531, ENSG00000237582, ENSG00000229094, ENSG00000233911, ENSG00000235068 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024406 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1408763.
- ^ Boyer et al. 2005.
- ^ S2CID 33012290.
- ^ Zeineddine, Dana et al. “The Oct4 protein: more than a magic stemness marker.” American journal of stem cells vol. 3,2 74-82. 5 Sep. 2014
- S2CID 2982527.
- PMID 25408886.
- PMID 30287838.
- S2CID 1913872.
- PMID 12727846.
- S2CID 1395518.
- ^ PMID 15860457.
- S2CID 1913872.
- ^ PMID 21663792.
- ^ Heurtier, V., Owens, N., Gonzalez, I. et al. The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells. Nat Commun 10, 1109 (2019). https://doi.org/10.1038/s41467-019-09041-z
- S2CID 459050.
- S2CID 4377572.
- PMID 18371336.
- S2CID 86129154.
- S2CID 4318637.
- S2CID 1630949.
- S2CID 1705950.
- PMID 31708402.
- ^ PMID 9528758.
- PMID 19968627.
- PMID 28953884.
- PMID 35762231.
- ^ For example:
- Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE (February 2005). "Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis". Carcinogenesis. 26 (2): 495–502. PMID 15513931.
- Kim JH, Jee MK, Lee SY, Han TH, Kim BS, Kang KS, Kang SK (September 2009). Mei L (ed.). "Regulation of adipose tissue stromal cells behaviors by endogenic Oct4 expression control". PLOS ONE. 4 (9): e7166. PMID 19777066.
- Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE (February 2005). "Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis". Carcinogenesis. 26 (2): 495–502.
- PMID 18159219.
- PMID 18239456.
- S2CID 23662657.
- PMID 21826175.
- S2CID 23516214.
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. 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. S2CID 27609337.
- Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y (February 2006). "G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis". Nature Cell Biology. 8 (2): 188–94. S2CID 23740530.
- Boyer, Laurie A.; Lee, Tong Ihn; Cole, Megan F.; Johnstone, Sarah E.; Levine, Stuart S.; Zucker, Jacob P.; Guenther, Matthew G.; Kumar, Roshan M.; Murray, Heather L.; Jenner, Richard G.; Gifford, David K.; Melton, Douglas A.; Jaenisch, Rudolf; Young, Richard A. (2005). "Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells". Cell. 122 (6). Elsevier BV: 947–956. 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. 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. 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. 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. 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. 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. 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. 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 (September 1996). "Generation and analysis of 280,000 human expressed sequence tags". Genome Research. 6 (9): 807–28. PMID 8889549.
- Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG (November 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. PMID 9368058.
- Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A (October 1998). "Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4". Cell. 95 (3): 379–91. S2CID 12892299.
- Gonzalez MI, Robins DM (March 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. PMID 11096094.
- Butteroni C, De Felici M, Schöler HR, Pesce M (December 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. PMID 11099378.
- Ezashi T, Ghosh D, Roberts RM (December 2001). "Repression of Ets-2-induced transactivation of the tau interferon promoter by Oct-4". Molecular and Cellular Biology. 21 (23): 7883–91. PMID 11689681.
- Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R (March 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. 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 (October 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. PMID 12841847.
- 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. PMID 12923055.
- Rajpert-De Meyts E, Hanstein R, Jørgensen N, Graem N, Vogt PH, Skakkebaek NE (June 2004). "Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads". Human Reproduction. 19 (6): 1338–44. 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. S2CID 35018708.
- Baal N, Reisinger K, Jahr H, Bohle RM, Liang O, Münstedt K, Rao CV, Preissner KT, Zygmunt MT (October 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. S2CID 4646923.
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