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Bioinformatics Analysis Makes Revelation to Potential Properties on Regulation and Functions of Human Sox2

  • Jianguo Zhang
  • Jianzhong Zhang
  • Wenqi Chen
  • Huiyu Li
  • Meiying Li
  • Lisha LiEmail author
Original Article
  • 35 Downloads

Abstract

Sex determining region Y-box 2 (Sox2) is a transcription factor that is essential for maintaining self-renewal or pluripotency of undifferentiated embryonic stem cells. The expression and distribution of Sox2 in tumor tissues have been extensively recorded, which are related to the progression and metastasis of tumor. However, a complete mechanistic understanding of Sox2 regulation and function remains to be studied. Herein, we show new potential properties of Sox2 regulation and functions from bioinformatics analysis. We use numerous algorithms to characterize the Sox2 gene promoter elements and the Sox2 protein structure, physio-chemical, localization properties and its evolutionary relationships. The expression of Sox2 is regulated by a diverse set of transcription factors and associated with the levels of methylation of CpG Islands in promoters. The structural properties of Sox2 indicate that Sox2 expresses as a stem cell marker in a variety of stem cells. Sox2 together with other transcription factors or proteins regulate the expression of downstream target genes, which makes a great difference to the biological function of stem cells. Not only stem cells, Sox2 also play an important role in tumor cells. In conclusion, this information from bioinformatics analysis will help to understand Sox2 regulation and functions better in future attempts.

Keywords

Bioinformatics analysis SOX2 Protein-protein interactions Proteomics Protein regulation 

Notes

Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant No. 31150007, 31201052), Jilin Province Science and Technology Development Program for Young Scientists Fund (Grant No. 20190103094JH), and Science and Technology Projects of the Education Department of Jilin Province (Grant No. [2016]445).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Sarkar A, Hochedlinger K (2013) The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12:15–30CrossRefGoogle Scholar
  2. 2.
    Rex M, Church R, Tointon K, Ichihashi RMA, Mokhtar S, Uwanogho D, Sharpe PT, Scotting PJ (1998) Granule cell development in the cerebellum is punctuated by changes in Sox gene expression. Mol Brain Res 55:28–34CrossRefGoogle Scholar
  3. 3.
    Adachi K, Nikaido I, Ohta H, Ohtsuka S, Ura H, Kadota M, Wakayama T, Ueda HR, Niwa H (2013) Context-dependent wiring of Sox2 regulatory networks for self-renewal of embryonic and trophoblast stem cells. Mol Cell 52:380–392CrossRefGoogle Scholar
  4. 4.
    Lin BY, Huang XF, Han X, Foltz G (2011) SOX2 (SRY (sex determining region Y)-box 2). Atlas Genet Cytogenet Oncol Haematol 15(12):1054–1057Google Scholar
  5. 5.
    Zhao X, Sun B, Sun D et al (2015) Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression. Oncol Rep 33:149–156CrossRefGoogle Scholar
  6. 6.
    Can T (2014) Introduction to bioinformatics. Methods Mol Biol 1107:51–71CrossRefGoogle Scholar
  7. 7.
    Eck RV, Dayhoff MO (1966) Evolution of the structure of ferredoxin based on living relics of primitive amino acid sequences. Science 152:363–366CrossRefGoogle Scholar
  8. 8.
    Reese MG (2001) Application of a time-delay neural network to promoter annotation in the Drosophila melanogaster genome. Comput Chem 26:51–56CrossRefGoogle Scholar
  9. 9.
    Li W, Cowley A, Uludag M, Gur T, McWilliam H, Squizzato S, Park YM, Buso N, Lopez R (2015) The EMBL-EBI bioinformatics web and programmatic tools framework. Nucleic Acids Res 43:W580–W584CrossRefGoogle Scholar
  10. 10.
    Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431CrossRefGoogle Scholar
  11. 11.
    Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba M (2002) PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics 18:333–334CrossRefGoogle Scholar
  12. 12.
    Wilkins MR, Gasteiger E, Bairoch A et al (1999) Protein identification and analysis tools in the ExPASy server. Methods Mol Biol 112:531–552Google Scholar
  13. 13.
    Geourjon C, Deleage G (1995) SOPMA: significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Comput Appl Biosci : CABIOS 11:681–684Google Scholar
  14. 14.
    Garnier J: GOR secondary structure prediction method version IV. Methods Enzymol, RF Doolittle Ed. 266: 540-553, 1998Google Scholar
  15. 15.
    Petersen TN, Brunak S, von Heijne G, Nielsen H (2011) SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 8:785–786CrossRefGoogle Scholar
  16. 16.
    Nguyen Ba AN, Pogoutse A, Provart N, Moses AM (2009) NLStradamus: a simple hidden Markov model for nuclear localization signal prediction. BMC Bioinf 10:202CrossRefGoogle Scholar
  17. 17.
    Emanuelsson O, Nielsen H, Brunak S, von Heijne G (2000) Predicting subcellular localization of proteins based on their N-terminal amino acid sequence. J Mol Biol 300:1005–1016CrossRefGoogle Scholar
  18. 18.
    Horton P, Park KJ, Obayashi T, Fujita N, Harada H, Adams-Collier CJ, Nakai K (2007) WoLF PSORT: protein localization predictor. Nucleic Acids Res 35:W585–W587CrossRefGoogle Scholar
  19. 19.
    Finn RD, Attwood TK, Babbitt PC, Bateman A, Bork P, Bridge AJ, Chang HY, Dosztányi Z, el-Gebali S, Fraser M, Gough J, Haft D, Holliday GL, Huang H, Huang X, Letunic I, Lopez R, Lu S, Marchler-Bauer A, Mi H, Mistry J, Natale DA, Necci M, Nuka G, Orengo CA, Park Y, Pesseat S, Piovesan D, Potter SC, Rawlings ND, Redaschi N, Richardson L, Rivoire C, Sangrador-Vegas A, Sigrist C, Sillitoe I, Smithers B, Squizzato S, Sutton G, Thanki N, Thomas PD, Tosatto SCE, Wu CH, Xenarios I, Yeh LS, Young SY, Mitchell AL (2017) InterPro in 2017-beyond protein family and domain annotations. Nucleic Acids Res 45:D190–D199CrossRefGoogle Scholar
  20. 20.
    Krogh A, Larsson B, von Heijne G, Sonnhammer EL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305:567–580CrossRefGoogle Scholar
  21. 21.
    Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258CrossRefGoogle Scholar
  22. 22.
    Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948CrossRefGoogle Scholar
  23. 23.
    Saldanha AJ (2004) Java Treeview-extensible visualization of microarray data. Bioinformatics 20:3246–3248CrossRefGoogle Scholar
  24. 24.
    Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452CrossRefGoogle Scholar
  25. 25.
    Johnson M, Zaretskaya I, Raytselis Y, Merezhuk Y, McGinnis S, Madden TL (2008) NCBI BLAST: a better web interface. Nucleic Acids Res 36:W5–W9CrossRefGoogle Scholar
  26. 26.
    Kumar S, Stecher G, Tamura K (2016) MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol 33:1870–1874CrossRefGoogle Scholar
  27. 27.
    Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M (2016) KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res 44:D457–D462CrossRefGoogle Scholar
  28. 28.
    Hackenberg M, Previti C, Luque-Escamilla PL, Carpena P, Martínez-Aroza J, Oliver JL (2006) CpGcluster: a distance-based algorithm for CpG-island detection. BMC Bioinf 7:446CrossRefGoogle Scholar
  29. 29.
    Wu Y, Guo Z, Wu H, Wang X, Yang L, Shi X, et al (2012) SUMOylation represses Nanog expression via modulating transcription factors Oct4 and Sox2. PLoS One 7(6):e39606Google Scholar
  30. 30.
    Orkin SH (2005) Chipping away at the embryonic stem cell network. Cell 122:828–830CrossRefGoogle Scholar
  31. 31.
    Zhao L, Zevallos SE, Rizzoti K, Jeong Y, Lovell-Badge R, Epstein DJ (2012) Disruption of SoxB1-dependent sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia. Dev Cell 22:585–596CrossRefGoogle Scholar
  32. 32.
    Bora-Singhal N, Nguyen J, Schaal C, Perumal D, Singh S, Coppola D, Chellappan S (2015) YAP1 regulates OCT4 activity and SOX2 expression to facilitate self-renewal and vascular mimicry of stem-like cells. Stem Cells 33:1705–1718CrossRefGoogle Scholar
  33. 33.
    Verma NK, Gadi A, Maurizi G, Roy UB, Mansukhani A, Basilico C (2017) Myeloid zinc finger 1 and GA binding protein co-operate with Sox2 in regulating the expression of yes-associated protein 1 in cancer cells. Stem Cells 35(12):2340–2350Google Scholar
  34. 34.
    Miranda CJ, Braun L, Jiang YY, Hester ME, Zhang L, Riolo M, Wang H, Rao M, Altura RA, Kaspar BK (2012) Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling. Aging Cell 11:542–552CrossRefGoogle Scholar
  35. 35.
    Seo E, Basu-Roy U, Zavadil J, Basilico C, Mansukhani A (2011) Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage. Mol Cell Biol 31:4593–4608CrossRefGoogle Scholar
  36. 36.
    Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM, et al (2010) Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS One 5(11):e13952Google Scholar
  37. 37.
    Piva M, Domenici G, Iriondo O, Rábano M, Simões BM, Comaills V, Barredo I, López-Ruiz JA, Zabalza I, Kypta R, Vivanco MM (2014) Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med 6:66–79CrossRefGoogle Scholar
  38. 38.
    Du J, Li B, Fang Y et al (2015) Overexpression of class III β-tubulin, Sox2, and nuclear Survivin is predictive of taxane resistance in patients with stage III ovarian epithelial cancer. BMC Cancer 15:536CrossRefGoogle Scholar
  39. 39.
    Li D, Zhao L-N, Zheng X-L et al (2014) Sox2 is involved in paclitaxel resistance of the prostate cancer cell line PC-3 via the PI3K/Akt pathway. Mol Med Rep 10:3169–3176CrossRefGoogle Scholar
  40. 40.
    Wen W, Han T, Chen C, Huang L, Sun W, Wang X, Chen SZ, Xiang DM, Tang L, Cao D, Feng GS, Wu MC, Ding J, Wang HY (2013) Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling. Mol Cancer Ther 12:1796–1804CrossRefGoogle Scholar
  41. 41.
    Chou M-Y, Hu F-W, Yu C-H, Yu C-C (2015) Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. Oral Oncol 51:31–39CrossRefGoogle Scholar
  42. 42.
    Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella-Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna JD, Brock MV, Seshagiri S (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44:1111–1116CrossRefGoogle Scholar
  43. 43.
    Chen S, Li X, Lu D et al (2013) SOX2 regulates apoptosis through MAP4K4-survivin signaling pathway in human lung cancer cells. Carcinogenesis 35:613–623CrossRefGoogle Scholar
  44. 44.
    Ji J, Zheng PS (2010) Expression of Sox2 in human cervical carcinogenesis. Hum Pathol 41:1438–1447CrossRefGoogle Scholar
  45. 45.
    Huang X, Xiong M, Jin Y et al (2016) Evidence that high-migration drug-surviving MOLT4 leukemia cells exhibit cancer stem cell-like properties. Int J Oncol 49:343–351CrossRefGoogle Scholar
  46. 46.
    Wang L, Yang H, Lei Z, Zhao J, Chen Y, Chen P, Li C, Zeng Y, Liu Z, Liu X, Zhang HT (2016) Repression of TIF1gamma by SOX2 promotes TGF-beta-induced epithelial-mesenchymal transition in non-small-cell lung cancer. Oncogene 35:867–877CrossRefGoogle Scholar
  47. 47.
    Tornin J, Martinez-Cruzado L, Santos L et al (2016) Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma. Oncotarget 7:30935–30950CrossRefGoogle Scholar
  48. 48.
    Marques-Torrejon MA, Porlan E, Banito A et al (2013) Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell 12:88–100CrossRefGoogle Scholar
  49. 49.
    Alonso MM, Diez-Valle R, Manterola L, Rubio A, Liu D, Cortes-Santiago N, Urquiza L, Jauregi P, de Munain AL, Sampron N, Aramburu A, Tejada-Solís S, Vicente C, Odero MD, Bandrés E, García-Foncillas J, Idoate MA, Lang FF, Fueyo J, Gomez-Manzano C (2011) Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS One 6:e26740CrossRefGoogle Scholar
  50. 50.
    Li X, Wang YK, Song ZQ, Du ZQ, Yang CX (2016) Dimethyl sulfoxide perturbs cell cycle progression and spindle Organization in Porcine Meiotic Oocytes. PLoS One 11:e0158074CrossRefGoogle Scholar
  51. 51.
    Jung K, Wu F, Wang P, Ye X, Abdulkarim BS, Lai R (2014) YB-1 regulates Sox2 to coordinately sustain stemness and tumorigenic properties in a phenotypically distinct subset of breast cancer cells. BMC Cancer 14:328CrossRefGoogle Scholar
  52. 52.
    Chien CS, Wang ML, Chu PY, Chang YL, Liu WH, Yu CC, Lan YT, Huang PI, Lee YY, Chen YW, Lo WL, Chiou SH (2015) Lin28B/Let-7 regulates expression of Oct4 and Sox2 and reprograms oral squamous cell carcinoma cells to a stem-like state. Cancer Res 75:2553–2565CrossRefGoogle Scholar
  53. 53.
    Wu QQ, Zhang LS, Su P, Lei X, Liu X, Wang H, Lu L, Bai Y, Xiong T, Li D, Zhu Z, Duan E, Jiang E, Feng S, Han M, Xu Y, Wang F, Zhou J (2015) MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling. Cell Res 25:1314–1332CrossRefGoogle Scholar
  54. 54.
    Lee Y, Kim KH, Kim DG, Cho HJ, Kim Y, Rheey J, Shin K, Seo YJ, Choi YS, Lee JI, Lee J, Joo KM, Nam DH (2015) FoxM1 promotes stemness and radio-resistance of glioblastoma by regulating the master stem cell regulator Sox2. PLoS One 10:e0137703CrossRefGoogle Scholar
  55. 55.
    Archer TC, Jin J, Casey ES (2011) Interaction of Sox1, Sox2, Sox3 and Oct4 during primary neurogenesis. Dev Biol 350:429–440CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  1. 1.The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune Medical CollegeJilin UniversityChangchunChina
  2. 2.Department of MedicineQingdao UniversityQingdaoChina

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