IN SILICO Analysis of SOX9 Deletion


Abstract views: 94 / PDF downloads: 64

Authors

  • Neslihan HEKİM Ondokuz Mayıs Üniversitesi

DOI:

https://doi.org/10.5281/zenodo.8404309

Keywords:

miRNA, miRWalk, SOX9

Abstract

SOX9 gene is a transcription factor that plays a key role in sex determination, chondrocyte differentiation and skeletal development in embryonic development. Decreased SOX9 expression often leads to campomelic dysplasia, a skeletal malformation syndrome observed with disorders of sex development. With their full or partial complementarity, miRNAs are important mediators that regulate the expression of their target transcripts. Deletion of SOX9 gene may result in increased expression levels of miRNAs targeting this gene and thus decreased expression levels of other target genes. This study aimed to identify miRNAs that deletion of SOX9 could potentially affect and their target genes in silico. For this, miRNAs targeting SOX9 gene were searched from the data stored with the machine learning algorithm using miRWalk database. Four miRNAs with scores greater than 0.95 and at least matching in the other two miRNA target databases (miRTarBase, miRDB, TargetScan) were identified from the results. The possible conformation of these miRNAs with SOX9 transcript was generated using the algorithms of STarMir and miRanda databases. The genes targeted by all four miRNAs were identified as RLIM, MBNL3, ZNF516 and FZD4 using miRDB. Using the GeneMANIA prediction server, 20 other genes with which these target genes interact were determined using association data, including protein and genetic interactions, pathways, co-expression and localization, and protein domain similarities. The expression in protein and RNA levels, molecular functions and roles in biological processes of these four target genes were investigated with human proteome data and experimental studies. The results of this study suggest the possibility that SOX9 gene deletion may cause expression changes in potential target genes via miRNA.

References

Brebi, P., Maldonado, L., Noordhuis, M. G., Ili, C., Leal, P., Garcia, P., . . . Guerrero-Preston, R. (2014). Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population. Epigenetics, 9(2), 308-317. doi:10.4161/epi.27120

Bustos, F., Espejo-Serrano, C., Segarra-Fas, A., Toth, R., Eaton, A. J., Kernohan, K. D., . . . Findlay, G. M. (2021). A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome. Sci Rep, 11(1), 9560. doi:10.1038/s41598-021-88911-3

Chen, L., Long, Y., Han, Z., Yuan, Z., Liu, W., Yang, F., . . . Zhong, Y. (2019). MicroRNA-101 inhibits cell migration and invasion in bladder cancer via targeting FZD4. Exp Ther Med, 17(2), 1476-1485. doi:10.3892/etm.2018.7084

E, J., Kang, Z., Yuan, J., Wang, Z., Tong, D., & Xing, J. (2022). ZNF516 suppresses stem cell-like characteristics by regulating the transcription of Sox2 in colorectal cancer. Am J Cancer Res, 12(8), 3745-3759. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/36119845

Gou, Y., Zhang, T., & Xu, J. (2015). Chapter Fifteen - Transcription Factors in Craniofacial Development: From Receptor Signaling to Transcriptional and Epigenetic Regulation. In Y. Chai (Ed.), Current Topics in Developmental Biology (Vol. 115, pp. 377-410): Academic Press.

Gu, Q., Tian, H., Zhang, K., Chen, D., Chen, D., Wang, X., & Zhao, J. (2018). Wnt5a/FZD4 Mediates the Mechanical Stretch-Induced Osteogenic Differentiation of Bone Mesenchymal Stem Cells. Cell Physiol Biochem, 48(1), 215-226. doi:10.1159/000491721

Haseeb, A., & Lefebvre, V. (2019). The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism. Nucleic Acids Res, 47(13), 6917-6931. doi:10.1093/nar/gkz523

Hekim, N., Ergün, S., & Güneş, S. (2021). Role of microRNAs in the pathophysiology of varicocele-related infertility. Andrology Bulletin, 23(4), 269-277. doi:10.24898/tandro.2021.76768

Huang, Y., Nie, M., Li, C., Zhao, Y., Li, J., Zhou, L., & Wang, L. (2017). RLIM suppresses hepatocellular carcinogenesis by up-regulating p15 and p21. Oncotarget, 8(47), 83075-83087. doi:10.18632/oncotarget.20904

Hyon, C., Chantot-Bastaraud, S., Harbuz, R., Bhouri, R., Perrot, N., Peycelon, M., . . . Bashamboo, A. (2015). Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD). Am J Med Genet A, 167A(8), 1851-1858. doi:10.1002/ajmg.a.37101

Ili, C., Lopez, J., Buchegger, K., Riquelme, I., Retamal, J., Zanella, L., . . . Brebi, P. (2019). Loss of ZNF516 protein expression is related with HR-HPV infection and cervical preneoplastic lesions. Arch Gynecol Obstet, 299(4), 1099-1108. doi:10.1007/s00404-018-5012-1

Jin, J. O., Lee, G. D., Nam, S. H., Lee, T. H., Kang, D. H., Yun, J. K., & Lee, P. C. (2021). Sequential ubiquitination of p53 by TRIM28, RLIM, and MDM2 in lung tumorigenesis. Cell Death Differ, 28(6), 1790-1803. doi:10.1038/s41418-020-00701-y

Kathrins, M., & Kolon, T. F. (2016). Malignancy in disorders of sex development. Transl Androl Urol, 5(5), 794-798. doi:10.21037/tau.2016.08.09

Katoh-Fukui, Y., Igarashi, M., Nagasaki, K., Horikawa, R., Nagai, T., Tsuchiya, T., . . . Fukami, M. (2015). Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9. Mol Genet Genomic Med, 3(6), 550-557. doi:10.1002/mgg3.165

Kushwaha, P., Kim, S., Foxa, G. E., Michalski, M. N., Williams, B. O., Tomlinson, R. E., & Riddle, R. C. (2020). Frizzled-4 is required for normal bone acquisition despite compensation by Frizzled-8. J Cell Physiol, 235(10), 6673-6683. doi:10.1002/jcp.29563

Lefebvre, V., Angelozzi, M., & Haseeb, A. (2019). SOX9 in cartilage development and disease. Curr Opin Cell Biol, 61, 39-47. doi:10.1016/j.ceb.2019.07.008

Li, L., Liu, X., He, L., Yang, J., Pei, F., Li, W., . . . Sun, L. (2017). ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin. Nat Commun, 8(1), 691. doi:10.1038/s41467-017-00702-5

N Antonakopoulos, D. V., N Loukas, Ch Christodoulaki, Z Iliodromiti, N Vrachnis. (2019). Campomelic dysplasia: an overview of a rare genetic disorder. An Obstetrics and Gynecology International Journal, 18 (3), 67-70.

Oladimeji, P. O., Bakke, J., Wright, W. C., & Chen, T. (2020). KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion. Sci Rep, 10(1), 1485. doi:10.1038/s41598-020-58448-y

Parker, K. L., & Schimmer, B. P. (2006). CHAPTER 8 - Embryology and Genetics of the Mammalian Gonads and Ducts. In J. D. Neill (Ed.), Knobil and Neill's Physiology of Reproduction (Third Edition) (pp. 313-336). St Louis: Academic Press.

Peng, J., Hou, Y., Wu, S., Li, Z., & Wu, Z. (2023). Knockout of Rlim Results in a Sex Ratio Shift toward Males but Superovulation Cannot Compensate for the Reduced Litter Size. Animals (Basel), 13(6). doi:10.3390/ani13061079

Pitzer, L. M., Moroney, M. R., Nokoff, N. J., & Sikora, M. J. (2021). WNT4 Balances Development vs Disease in Gynecologic Tissues and Women's Health. Endocrinology, 162(7). doi:10.1210/endocr/bqab093

Ragitha, T. S., Sunish, K. S., Gilvaz, S., Daniel, S., Varghese, P. R., Raj, S., . . . Suresh Kumar, R. (2023). Mutation analysis of WNT4 gene in SRY negative 46,XX DSD patients with Mullerian agenesis and/or gonadal dysgenesis- An Indian study. Gene, 861, 147236. doi:10.1016/j.gene.2023.147236

Rey, R. A., & Josso, N. (2016). Chapter 119 - Diagnosis and Treatment of Disorders of Sexual Development∗. In J. L. Jameson, L. J. De Groot, D. M. de Kretser, L. C. Giudice, A. B. Grossman, S. Melmed, J. T. Potts, & G. C. Weir (Eds.), Endocrinology: Adult and Pediatric (Seventh Edition) (pp. 2086-2118.e2085). Philadelphia: W.B. Saunders.

Rockich, B. E., Hrycaj, S. M., Shih, H. P., Nagy, M. S., Ferguson, M. A. H., Kopp, J. L., . . . Spence, J. R. (2013). Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proceedings of the National Academy of Sciences, 110(47), E4456-E4464. doi:doi:10.1073/pnas.1311847110

Schluth-Bolard, C., Ottaviani, A., Gilson, E., & Magdinier, F. (2011). Chapter 6 - Chromosomal Position Effects and Gene Variegation: Impact in Pathologies. In T. Tollefsbol (Ed.), Handbook of Epigenetics (pp. 77-105). San Diego: Academic Press.

Sun, X., Diao, X., Zhu, X., Yin, X., & Cheng, G. (2021). Nanog-mediated stem cell properties are critical for MBNL3-associated paclitaxel resistance of ovarian cancer. J Biochem, 169(6), 747-756. doi:10.1093/jb/mvab021

Wang, F., Gervasi, M. G., Boskovic, A., Sun, F., Rinaldi, V. D., Yu, J., . . . Bach, I. (2021). Deficient spermiogenesis in mice lacking Rlim. Elife, 10. doi:10.7554/eLife.63556

Yang, T. L., Guo, Y., Li, J., Zhang, L., Shen, H., Li, S. M., . . . Deng, H. W. (2013). Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density. J Bone Miner Res, 28(4), 828-837. doi:10.1002/jbmr.1788

Yu, Z., Wang, G., Zhang, C., Liu, Y., Chen, W., Wang, H., & Liu, H. (2020). LncRNA SBF2-AS1 affects the radiosensitivity of non-small cell lung cancer via modulating microRNA-302a/MBNL3 axis. Cell Cycle, 19(3), 300-316. doi:10.1080/15384101.2019.1708016

Yuan, J. H., Liu, X. N., Wang, T. T., Pan, W., Tao, Q. F., Zhou, W. P., . . . Sun, S. H. (2017). The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1. Nat Cell Biol, 19(7), 820-832. doi:10.1038/ncb3538

Zhang, K., Lv, Q., Li, L., Jiang, M., & Fang, F. (2021). Discovering the Role of FZD4 Gene in Human Cutaneous Squamous Cell Carcinoma. Indian J Dermatol, 66(5), 484-489. doi:10.4103/ijd.ijd_1147_20

Zhou, J., Liu, T., Xu, H., Wang, Y., Yang, T., & Liu, L. (2022). LncRNA FIRRE promotes the proliferation and metastasis of hepatocellular carcinoma by regulating the expression of PXN through interacting with MBNL3. Biochem Biophys Res Commun, 625, 188-195. doi:10.1016/j.bbrc.2022.07.099

Zhou, J. G., Hua, Y., Liu, S. W., Hu, W. Q., Qian, R., & Xiong, L. (2020). MicroRNA-1286 inhibits osteogenic differentiation of mesenchymal stem cells to promote the progression of osteoporosis via regulating FZD4 expression. Eur Rev Med Pharmacol Sci, 24(1), 1-10. doi:10.26355/eurrev_202001_19889

Zhou, X., Jiang, J., & Guo, S. (2021). Hsa_circ_0004712 downregulation attenuates ovarian cancer malignant development by targeting the miR-331-3p/FZD4 pathway. J Ovarian Res, 14(1), 118. doi:10.1186/s13048-021-00859-0

Published

2023-10-04

How to Cite

HEKİM , N. (2023). IN SILICO Analysis of SOX9 Deletion. GEVHER NESIBE JOURNAL OF MEDICAL AND HEALTH SCIENCES, 8(Özel Sayı), 826–832. https://doi.org/10.5281/zenodo.8404309

Issue

Section

Articles