Biology:Oct-4

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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. It 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]

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.[4] 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.[5] 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.[6] 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.[7] 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.[8]

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.[9] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal.[10] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[11]

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.[12]

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.[3] 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.[13] 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[14] (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells.[11] 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.[13]

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,[15][16][17] 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.[18] It was later determined that only two of these four factors, namely Oct4 and Klf4, are sufficient to reprogram mouse adult neural stem cells.[19] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.[20] 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.[21] 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.[22] 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 promoter of Rex1. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[23] However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1.[23] 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.[24]
  • CRISPR-Cas9 knockout of the gene in human embryonic stem cells demonstrated that Oct-4 is essential for the development after fertilisation.[25]
  • 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. [26]

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.).[27] Other scientists have produced evidence to the contrary,[28] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[29] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[30] Oct-4 has also been implicated as a marker of cancer stem cells.[31][32]

See also


References

  1. ↑ "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. September 1992. doi:10.1093/nar/20.17.4613. PMID 1408763. 
  2. ↑ Boyer et al. 2005.
  3. ↑ 3.0 3.1 "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nature Genetics 24 (4): 372–6. April 2000. doi:10.1038/74199. PMID 10742100. 
  4. ↑ 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
  5. ↑ PAN, Guang Jin; CHANG, Zeng Yi; SCHÖLER, Hans R.; PEI, Duanqing (2002). "Stem cell pluripotency and transcription factor Oct4". Cell Research (Springer Science and Business Media LLC) 12 (5–6): 321–329. doi:10.1038/sj.cr.7290134. ISSN 1001-0602. PMID 12528890. 
  6. ↑ Wu, Guangming; Schöler, Hans R (2014). "Role of Oct4 in the early embryo development". Cell Regeneration (Springer Science and Business Media LLC) 3 (1): 3:7. doi:10.1186/2045-9769-3-7. ISSN 2045-9769. PMID 25408886. 
  7. ↑ Saha, Subbroto Kumar; Jeong, Yeojin; Cho, Sungha; Cho, Ssang-Goo (2018-10-04). "Systematic expression alteration analysis of master reprogramming factor OCT4 and its three pseudogenes in human cancer and their prognostic outcomes". Scientific Reports (Springer Science and Business Media LLC) 8 (1): 14806. doi:10.1038/s41598-018-33094-7. ISSN 2045-2322. PMID 30287838. Bibcode: 2018NatSR...814806S. 
  8. ↑ Hochedlinger, Konrad; Yamada, Yasuhiro; Beard, Caroline; Jaenisch, Rudolf (2005). "Ectopic Expression of Oct-4 Blocks Progenitor-Cell Differentiation and Causes Dysplasia in Epithelial Tissues". Cell (Elsevier BV) 121 (3): 465–477. doi:10.1016/j.cell.2005.02.018. ISSN 0092-8674. PMID 15882627. 
  9. ↑ "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research 63 (9): 2244–50. May 2003. PMID 12727846. 
  10. ↑ "High-efficiency RNA interference in human embryonic stem cells". Stem Cells 23 (3): 299–305. March 2005. doi:10.1634/stemcells.2004-0252. PMID 15749924. 
  11. ↑ 11.0 11.1 "Transcriptional regulation of nanog by OCT4 and SOX2". The Journal of Biological Chemistry 280 (26): 24731–7. July 2005. doi:10.1074/jbc.M502573200. PMID 15860457. 
  12. ↑ "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell 121 (3): 465–77. May 2005. doi:10.1016/j.cell.2005.02.018. PMID 15882627. 
  13. ↑ 13.0 13.1 "Pluripotency factors in embryonic stem cells regulate differentiation into germ layers". Cell 145 (6): 875–89. June 2011. doi:10.1016/j.cell.2011.05.017. PMID 21663792. 
  14. ↑ 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
  15. ↑ "Generation of germline-competent induced pluripotent stem cells". Nature 448 (7151): 313–7. July 2007. doi:10.1038/nature05934. PMID 17554338. Bibcode: 2007Natur.448..313O. 
  16. ↑ "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature 448 (7151): 318–24. July 2007. doi:10.1038/nature05944. PMID 17554336. Bibcode: 2007Natur.448..318W. 
  17. ↑ "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution". Cell Stem Cell 1 (1): 55–70. June 2007. doi:10.1016/j.stem.2007.05.014. PMID 18371336. 
  18. ↑ "Induced pluripotent stem cell lines derived from human somatic cells". Science 318 (5858): 1917–20. December 2007. doi:10.1126/science.1151526. PMID 18029452. Bibcode: 2007Sci...318.1917Y. 
  19. ↑ "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature 454 (7204): 646–50. July 2008. doi:10.1038/nature07061. PMID 18594515. Bibcode: 2008Natur.454..646K. 
  20. ↑ "Oct4-induced pluripotency in adult neural stem cells". Cell 136 (3): 411–9. February 2009. doi:10.1016/j.cell.2009.01.023. PMID 19203577. 
  21. ↑ "Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts". Nature Biotechnology 26 (1): 101–6. January 2008. doi:10.1038/nbt1374. PMID 18059259. 
  22. ↑ "Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs". Cell Stem Cell 25 (6): 737–753.e4. December 2019. doi:10.1016/j.stem.2019.10.002. PMID 31708402. 
  23. ↑ 23.0 23.1 "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. April 1998. doi:10.1128/mcb.18.4.1866. PMID 9528758. 
  24. ↑ "Oct-4 controls cell-cycle progression of embryonic stem cells". The Biochemical Journal 426 (2): 171–81. February 2010. doi:10.1042/BJ20091439. PMID 19968627. 
  25. ↑ "Genome editing reveals a role for OCT4 in human embryogenesis". Nature 550 (7674): 67–73. October 2017. doi:10.1038/nature24033. PMID 28953884. Bibcode: 2017Natur.550...67F. 
  26. ↑ Bernard, Laure D; Dubois, Agnès; Heurtier, Victor; Fischer, Véronique; Gonzalez, Inma; Chervova, Almira; Tachtsidi, Alexandra; Gil, Noa et al. (28 June 2022). "OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency". Nucleic Acids Research 50 (13): 7367–7379. doi:10.1093/nar/gkac550. ISSN 0305-1048. PMID 35762231. 
  27. ↑ For example:
  28. ↑ "Oct4 expression is not required for mouse somatic stem cell self-renewal". Cell Stem Cell 1 (4): 403–15. October 2007. doi:10.1016/j.stem.2007.07.020. PMID 18159219. 
  29. ↑ "The pluripotency regulator Oct4: a role in somatic stem cells?". Cell Cycle 7 (6): 725–8. March 2008. doi:10.4161/cc.7.6.5573. PMID 18239456. http://www.landesbioscience.com/journals/cc/article/5573/. 
  30. ↑ "Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker". Stem Cells 25 (7): 1675–80. July 2007. doi:10.1634/stemcells.2006-0611. PMID 17379765. 
  31. ↑ "OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer". Laboratory Animal Research 27 (2): 147–52. June 2011. doi:10.5625/lar.2011.27.2.147. PMID 21826175. 
  32. ↑ "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer 120 (7): 1598–602. April 2007. doi:10.1002/ijc.22508. PMID 17205510. 

Further reading

External links



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