Introduction

Oct4 and Sox2 are two transcription factors (TFs) involved in various roles in murine and primate cells, mainly related to the maintenance of pluripotency and self-renewal properties in embryonic stem cells. These two factors, encoded by the POU5F1 (POU Class 5 Homeobox 1) and SOX2 (SRY-Box Transcription Factor 2) genes, respectively, serve as repprogramming TFs and occupy the same target genes in vivo ^[1][2], forming the complex OCT4-SOX2, which is the main way in which they act, although they are not obligate heterodimers in solution.

OCT4

The OCT4 transcription factor (octamer-binding transcription factor 4), also known as OCT-3, OCT3 / 4, OTF3 or NF-A3, was discovered almost three decades ago, where its use relationship with pluripotent CTE in primate and rodent species ^[3]. This protein is encoded by the POU5F1 gene, which is located on chromosome 6 in humans and 17 in rats, and belongs to the POU family (Pit, October, Unc) of DNA-binding proteins, which regulate the expression of target genes ^[4][5]. In humans, through alternative splicing, POU5F1 generates less than eight distinct RNA transcripts, these being OCT4A, OCT4B-190, OCT4B-265, OCT4B-164, OCT4B1 and more recently reported as OCT4C, OCT4C1 and OCT4B4 variants ^[6]. In addition to the generated isoforms, many studies have been carried out mainly with respect to the functions of the OCT4A isoform. Studies targeting the OCT4B isoforms (190, 265 and 164) that are not able to support an automatic restoration of the CTE, but they can respond to cellular stress, whereas the functions of OCT4B1, OCT4C and OCT4C1 have not yet been clarified^[7]. OCT4A is normally expressed in the early stages of embryonic development and represents one of the main regulatory factors for pluripotency and self-review of embryonic stem cells, being considered a marker of pluripotency^[8]. A further differentiation of CTE into cells used for different tissues depends on rapid and rapid expression of OCT4A, and these cells are differentiated remain with the OCT4A factor silenced ^[9][10][11]. However, we have already documented an open expression of transcription factors such as OCT4, SOX2 and NANOG, together or controlled, lead to tumors, metastases and the greatest recurrence after use, in different types of cancer ^[12].

SOX2

The SOX/Sox (SRY homology box) family of proteins comprises 20 individual members in man and mouse ^[13], which SOX2 is the most explored. SOX proteins are principally defined by a conserved DNA-binding element, the so-called high mobility group (HMG) that relates to a transcriptional master regulator of virility (i.e., SEX determining factor Y, SRY) and thus functionally qualifies SOX/Sox proteins as DNA-binders ^[14][15]. While Sox proteins contribute to various cellular functionalities, reprogramming capacity is largely confined to members of the SoxB1 group (i.e., Sox1, Sox2, and Sox3)^[16]. SOX2 significantly often imposes transcription modulatory in conjunction with co-factors, such as Oct3/4. OCT3/4 in ES cells

Embryonic Expression

OCT4

In humans, the POUF5F1 alternative splicing gives rise to two Oct4 isoforms, Oct4-IA and Oct4-IB, that differs by the N-terminal region. Oct4-IA is required to self-renewal maintenance of stem cells and Oct4-IB is not related to stemness ^{[17] [18]}. Oct4 is present in all stages of embryo development ^{[19] [20] [21]}. The Oct4 expression pattern differs between the blastomeres in the same development stage by the protein cytoplasmic localization^[22]. From the unfertilized oocyte to the solid morula no Oct4 protein is observed in the nucleus ^[22]. During compaction, Oct4 expression becomes ubiquitous and abundant in the nucleus of all morula blastomeres ^[22]. In the blastocyst, the Oct4 mRNA and protein are present in the inner cell mass ^[21].

Maternal murine Oct4 mRNA and protein are deposited in the oocyte and they are necessary for the development until the stage of 4 cells. Proteins are present at low levels at these early stages of murine embryogenesis. Transcription of zygotic Pou5f1 gene is activated at the 4 to 8-cell stage ^{[23] [24] [25] [26]}. With the blastocyst is formation, the expression of Oct4 remains high in the inner cell mass and it is not observed in the trophectoderm. After the murine embryo implantation, the transient upregulation of Oct4 in a subset of cells from the inner cell mass, triggers their differentiation into hypoblast (primitive endoderm). After that, the Oct4 expression decreases in these cells ^{[23] [24] [25] [26]}. During gastrulation, Oct4 is down-regulated and, after day 8 of gestation, it is confined to primordial germ cells ^{[23] [25] [27] [28]}.

SOX2

Sox2 is persistently expressed during embryonic development and it is first expressed in the morula stage. Later it becomes specifically located in the inner cell mass of blastocyst and epiblast ^[29]. After gastrulation it is predominantly expressed in the central nervous system ^[30]. It is known that zygotic deletion of Sox2 is lethal due to the failure to form pluripotent epiblast whilst the absence of Sox2 has little effect on the trophectoderm formation ^[29]. The depletion of Sox2 compromised the stemness of both mouse and human embryonic stem cells, changing their morphology and pluripotent marker expression and they differentiate primarily into trophectoderm ^{[31] [32]}.

The OCT4-SOX2 mechanism in the nucleosome

The nucleosome is the chromatin basic unit, composed of a 147 pb DNA segment wrapped around 8 histone proteins. It is a convention that the sites in which a DNA major groove is pointed to the nucleosome core are called "superhelix location" (SHL). The SHL are enumerated from 0 to ±7, having 0 as the nucleosome main axis, known as "dyad". The OCT4-SOX2 binds in the SHL-6 site (Fig 1)^[33] and both of them act in the DNA removal from the core histones ^[34]. OCT4 has a bipartite DNA binding domain (DBD) comprised of a POU-specific (POUS) and POU-homeo-domain (POUHD) separated by 17-residues (Fig 2) and SOX2 has a high-mobility group (HMG) domain (Fig 2) ^{[33] [34] [26]}. The OCT4-POUS and SOX2-HMG DBDs engage major and minor grooves, respectively ^[34]. The DNA remains attached and straightened around the OCT4 site but is detached around the SOX2 motif ^[34].

OCT4 recognizes a partial motif, engaging DNA with its POUS domain, whereas the POUHD is not engaged ^[33]. On free DNA, both POU domains engage the major groove over 8bp on opposite sides of the DNA ^[34]. SOX2 competes with histones for DNA binding and kinks DNA by ~90° at SHL-6.5 away from the histones ^[26]. This is accomplished by intercalation of the SOX2 Phe48 and Met49 ‘wedge’ at the TT base step ^[26]. SOX2 kinks the DNA and synergistically with OCT4 releases the DNA from the core histones Movie1^[33].

Figure 1 - Extracted from the article Mechanisms of OCT4-SOX2 motif readout on nucleosomes (Alicia K. Michael et al., 2020)^[33]. (B) OCT4-SOX2-NCPSHL+6 model.

Figure 2 - Extracted from the article Mechanisms of OCT4-SOX2 motif readout on nucleosomes (Alicia K. Michael et al., 2020)^[33]. (A) Domain schematic of OCT4 and SOX2 constructs.

Gatekeeper for embryonic stem cell pluripotency

The pluripotent identity is ruled by transcriptional factor such as Oct4 and Sox2, that act as key pluripotency regulators among the mammals ^[35]. Oct4 keeps the undifferentiated cells from becoming trophoblast or endoderm ^[35] and Sox2 is critical in the formation of pluripotent epiblast cells ^[36]. The forced expression of Oct4 in Sox2-null mouse embryonic stem cells can rescue the pluripotency, indicating that the role of Sox2 in maintaining the pluripotent state of embryonic stem cells is primarily to sustain a sufficient level of Oct4 expression ^{[31] [32]}. Oct4 and Sox2 cooperate to keep the pluripotency of embryonic stem cells by co-occupying a large number of enhancers and/or promoters and regulating the expression levels of their target genes ^[36]. They activate the transcription of genes involved in the self renewal of embryonic stem cells and besides, they bind themselves to the promoters of their own genes activating them ^[35].

iPSC/Yamanaka factors

In 2006, Yamanaka and Takahashi first demonstrated the factors necessary for the induced Pluripotent Stem Cells (iPSC) generation. The Yamanaka factors, including Oct3/4 and Sox2 (also Klf4 and c-Myc), represent an important milestone in life sciences and have been widely used in the research and medical fields ^[37].

Related Diseases

Tumorigenicity

Since these factors are straightly related to pluripotency regulation in stem cells, it has been documented that an aberrant expression of this TF's, together or separately, lead to tumorigenesis, metastasis and even greater recurrence after treatments in different types of cancer ^[38]. The increased expression of OCT4 was correlated with poorer survival and greater aggressiveness in bladder tumors^[39], hepatocellular carcinoma^[40], breast^[41], pancreas^[42], among others.

References

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2. ↑ Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008 Jun 13;133(6):1106-17. doi: 10.1016/j.cell.2008.04.043. PMID:18555785 doi:http://dx.doi.org/10.1016/j.cell.2008.04.043
3. ↑ Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014 Sep 5;3(2):74-82. eCollection 2014. PMID:25232507
4. ↑ Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014 Sep 5;3(2):74-82. eCollection 2014. PMID:25232507
5. ↑ Malakootian M, Mirzadeh Azad F, Naeli P, Pakzad M, Fouani Y, Taheri Bajgan E, Baharvand H, Mowla SJ. Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. Eur J Cell Biol. 2017 Jun;96(4):347-355. doi: 10.1016/j.ejcb.2017.03.009. Epub, 2017 Apr 10. PMID:28476334 doi:http://dx.doi.org/10.1016/j.ejcb.2017.03.009
6. ↑ Malakootian M, Mirzadeh Azad F, Naeli P, Pakzad M, Fouani Y, Taheri Bajgan E, Baharvand H, Mowla SJ. Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. Eur J Cell Biol. 2017 Jun;96(4):347-355. doi: 10.1016/j.ejcb.2017.03.009. Epub, 2017 Apr 10. PMID:28476334 doi:http://dx.doi.org/10.1016/j.ejcb.2017.03.009
7. ↑ Wang X, Dai J. Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells. 2010 May;28(5):885-93. doi: 10.1002/stem.419. PMID:20333750 doi:http://dx.doi.org/10.1002/stem.419
8. ↑ da Silva PBG, Teixeira Dos Santos MC, Rodini CO, Kaid C, Pereira MCL, Furukawa G, da Cruz DSG, Goldfeder MB, Rocha CRR, Rosenberg C, Okamoto OK. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells. Oncotarget. 2017 Mar 21;8(12):19192-19204. doi: 10.18632/oncotarget.15163. PMID:28186969 doi:http://dx.doi.org/10.18632/oncotarget.15163
9. ↑ Villodre ES, Kipper FC, Pereira MB, Lenz G. Roles of OCT4 in tumorigenesis, cancer therapy resistance and prognosis. Cancer Treat Rev. 2016 Dec;51:1-9. doi: 10.1016/j.ctrv.2016.10.003. Epub 2016 Oct, 14. PMID:27788386 doi:http://dx.doi.org/10.1016/j.ctrv.2016.10.003
10. ↑ Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW. OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells. 2008 Dec;26(12):3068-74. doi: 10.1634/stemcells.2008-0530. Epub 2008 , Sep 11. PMID:18787205 doi:http://dx.doi.org/10.1634/stemcells.2008-0530
11. ↑ Hatefi N, Nouraee N, Parvin M, Ziaee SA, Mowla SJ. Evaluating the expression of oct4 as a prognostic tumor marker in bladder cancer. Iran J Basic Med Sci. 2012 Nov;15(6):1154-61. PMID:23653844
12. ↑ Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014 Sep 5;3(2):74-82. eCollection 2014. PMID:25232507
13. ↑ Schepers GE, Teasdale RD, Koopman P. Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell. 2002 Aug;3(2):167-70. doi: 10.1016/s1534-5807(02)00223-x. PMID:12194848 doi:http://dx.doi.org/10.1016/s1534-5807(02)00223-x
14. ↑ Bowles J, Schepers G, Koopman P. Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol. 2000 Nov 15;227(2):239-55. doi: 10.1006/dbio.2000.9883. PMID:11071752 doi:http://dx.doi.org/10.1006/dbio.2000.9883
15. ↑ Schaefer T, Lengerke C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond. Oncogene. 2020 Jan;39(2):278-292. doi: 10.1038/s41388-019-0997-x. Epub 2019 Sep, 2. PMID:31477842 doi:http://dx.doi.org/10.1038/s41388-019-0997-x
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23. ↑ ^{23.0 23.1 23.2} Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998 Oct 30;95(3):379-91. doi: 10.1016/s0092-8674(00)81769-9. PMID:9814708 doi:http://dx.doi.org/10.1016/s0092-8674(00)81769-9
24. ↑ ^{24.0 24.1} Palmieri SL, Peter W, Hess H, Scholer HR. Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. Dev Biol. 1994 Nov;166(1):259-67. doi: 10.1006/dbio.1994.1312. PMID:7958450 doi:http://dx.doi.org/10.1006/dbio.1994.1312
25. ↑ ^{25.0 25.1 25.2} Pesce M, Scholer HR. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells. 2001;19(4):271-8. doi: 10.1634/stemcells.19-4-271. PMID:11463946 doi:http://dx.doi.org/10.1634/stemcells.19-4-271
26. ↑ ^{26.0 26.1 26.2 26.3 26.4} Jerabek S, Merino F, Scholer HR, Cojocaru V. OCT4: dynamic DNA binding pioneers stem cell pluripotency. Biochim Biophys Acta. 2014 Mar;1839(3):138-54. doi: 10.1016/j.bbagrm.2013.10.001., Epub 2013 Oct 18. PMID:24145198 doi:http://dx.doi.org/10.1016/j.bbagrm.2013.10.001
27. ↑ Pan GJ, Chang ZY, Scholer HR, Pei D. Stem cell pluripotency and transcription factor Oct4. Cell Res. 2002 Dec;12(5-6):321-9. doi: 10.1038/sj.cr.7290134. PMID:12528890 doi:http://dx.doi.org/10.1038/sj.cr.7290134
28. ↑ Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M, Lomeli H, Nagy A, McLaughlin KJ, Scholer HR, Tomilin A. Oct4 is required for primordial germ cell survival. EMBO Rep. 2004 Nov;5(11):1078-83. doi: 10.1038/sj.embor.7400279. PMID:15486564 doi:http://dx.doi.org/10.1038/sj.embor.7400279
29. ↑ ^{29.0 29.1} Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003 Jan 1;17(1):126-40. doi: 10.1101/gad.224503. PMID:12514105 doi:http://dx.doi.org/10.1101/gad.224503
30. ↑ Wegner M, Stolt CC. From stem cells to neurons and glia: a Soxist's view of neural development. Trends Neurosci. 2005 Nov;28(11):583-8. doi: 10.1016/j.tins.2005.08.008. Epub, 2005 Aug 31. PMID:16139372 doi:http://dx.doi.org/10.1016/j.tins.2005.08.008
31. ↑ ^{31.0 31.1} Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov AA, Ko MS, Niwa H. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol. 2007 Jun;9(6):625-35. doi: 10.1038/ncb1589. Epub 2007 May 21. PMID:17515932 doi:http://dx.doi.org/10.1038/ncb1589
32. ↑ ^{32.0 32.1} Fong H, Hohenstein KA, Donovan PJ. Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells. 2008 Aug;26(8):1931-8. doi: 10.1634/stemcells.2007-1002. Epub 2008, Apr 3. PMID:18388306 doi:http://dx.doi.org/10.1634/stemcells.2007-1002
33. ↑ ^{33.0 33.1 33.2 33.3 33.4 33.5} Michael AK, Grand RS, Isbel L, Cavadini S, Kozicka Z, Kempf G, Bunker RD, Schenk AD, Graff-Meyer A, Pathare GR, Weiss J, Matsumoto S, Burger L, Schubeler D, Thoma NH. Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science. 2020 Apr 23. pii: science.abb0074. doi: 10.1126/science.abb0074. PMID:32327602 doi:http://dx.doi.org/10.1126/science.abb0074
34. ↑ ^{34.0 34.1 34.2 34.3 34.4} Soufi A, Garcia MF, Jaroszewicz A, Osman N, Pellegrini M, Zaret KS. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell. 2015 Apr 23;161(3):555-568. doi: 10.1016/j.cell.2015.03.017. Epub 2015 Apr , 16. PMID:25892221 doi:http://dx.doi.org/10.1016/j.cell.2015.03.017
35. ↑ ^{35.0 35.1 35.2} Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014 Sep 5;3(2):74-82. eCollection 2014. PMID:25232507
36. ↑ ^{36.0 36.1} Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells. 2014 Jul 26;6(3):305-11. doi: 10.4252/wjsc.v6.i3.305. PMID:25126380 doi:http://dx.doi.org/10.4252/wjsc.v6.i3.305
37. ↑ Yamanaka S, Takahashi K. [Induction of pluripotent stem cells from mouse fibroblast cultures]. Tanpakushitsu Kakusan Koso. 2006 Dec;51(15):2346-51. PMID:17154061
38. ↑ Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014 Sep 5;3(2):74-82. eCollection 2014. PMID:25232507
39. ↑ Hatefi N, Nouraee N, Parvin M, Ziaee SA, Mowla SJ. Evaluating the expression of oct4 as a prognostic tumor marker in bladder cancer. Iran J Basic Med Sci. 2012 Nov;15(6):1154-61. PMID:23653844
40. ↑ Dong Z, Zeng Q, Luo H, Zou J, Cao C, Liang J, Wu D, Liu L. Increased expression of OCT4 is associated with low differentiation and tumor recurrence in human hepatocellular carcinoma. Pathol Res Pract. 2012 Sep 15;208(9):527-33. doi: 10.1016/j.prp.2012.05.019. Epub, 2012 Jul 21. PMID:22824146 doi:http://dx.doi.org/10.1016/j.prp.2012.05.019
41. ↑ Hassiotou F, Hepworth AR, Beltran AS, Mathews MM, Stuebe AM, Hartmann PE, Filgueira L, Blancafort P. Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland. Front Oncol. 2013 Apr 11;3:79. doi: 10.3389/fonc.2013.00079. eCollection 2013. PMID:23596564 doi:http://dx.doi.org/10.3389/fonc.2013.00079
42. ↑ Wen J, Park JY, Park KH, Chung HW, Bang S, Park SW, Song SY. Oct4 and Nanog expression is associated with early stages of pancreatic carcinogenesis. Pancreas. 2010 Jul;39(5):622-6. doi: 10.1097/MPA.0b013e3181c75f5e. PMID:20173672 doi:http://dx.doi.org/10.1097/MPA.0b013e3181c75f5e

^[1] Zeineddine D, Hammoud AA, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014;3(2):74-82. Published 2014 Sep 5. ^[2] Malakootian M, Mirzadeh Azad F, Naeli P, et al. Novel spliced variants of OCT4, OCT4C and OCT4C1, with distinct expression patterns and functions in pluripotent and tumor cell lines. Eur J Cell Biol. 2017;96(4):347-355. doi:10.1016/j.ejcb.2017.03.009 ^[3] Wang X, Dai J. Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells. 2010;28(5):885-893. doi:10.1002/stem.419 ^[4] da Silva PBG, Teixeira Dos Santos MC, Rodini CO, et al. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells. Oncotarget. 2017;8(12):19192-19204. doi:10.18632/oncotarget.15163 ^[5] Atlasi Y, Mowla SJ, Ziaee SA, Gokhale PJ, Andrews PW. OCT4 spliced variants are differentially expressed in human pluripotent and nonpluripotent cells. Stem Cells. 2008;26(12):3068-3074. doi:10.1634/stemcells.2008-0530 ^[6] Hatefi N, Nouraee N, Parvin M, Ziaee SA, Mowla SJ. Evaluating the expression of oct4 as a prognostic tumor marker in bladder cancer. Iran J Basic Med Sci. 2012;15(6):1154-1161. ^[7]Dong Z, Zeng Q, Luo H, et al. Increased expression of OCT4 is associated with low differentiation and tumor recurrence in human hepatocellular carcinoma. Pathol Res Pract. 2012;208(9):527-533. doi:10.1016/j.prp.2012.05.019 ^[8]Hassiotou F, Hepworth AR, Beltran AS, et al. Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland. Front Oncol. 2013;3:79. Published 2013 Apr 11. doi:10.3389/fonc.2013.00079 ^[9]Wen J, Park JY, Park KH, et al. Oct4 and Nanog expression is associated with early stages of pancreatic carcinogenesis. Pancreas. 2010;39(5):622-626. doi:10.1097/MPA.0b013e3181c75f5e ^{[10] [11]}

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