In silico Analysis of Possible Novel RNA Interactions and Deleterious Single Nucleotide Polymorphisms Related to MSX2, SHH, SMAD7 and TFAP2 Genes Involved in Odontogenesis

Document Type : Research Article

Authors

Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran

Abstract

Identification of gene expression profiles, RNA interactions, gene regulation patterns, and single nucleotide polymorphisms (SNPs) is important for determining the molecular mechanisms underlying the normal odontogenesis and the pathology of oral and dental disorders. Therefore, this in silico study aimed to identify novel proteins, RNA interactions, and deleterious SNPs related to four major genes (MSX2, SHH, SMAD7, TFAP2) involved in the odontogenesis process. After pathway enrichment and gene ontology analysis, the protein-protein, microRNA (miRNA)-mRNA, and miRNA-long noncoding RNA (lncRNA) interactions and networks were determined for the selected genes using integrated bioinformatics analyses. Moreover, the potential deleterious SNPs in the selected genes were identified and finally, their validation and implications on the structure of proteins were investigated by specific bioinformatics tools. The results of this study introduced UBE2I, RNF111, MYBL2, and VEGFA as novel factors that may involve in odontogenesis. It was also found that the MSX2, SHH, and TFAP2A are targeted by hsa-miR-6775-5p, hsa-miR-149-3p, and hsa-miR-432-5p, respectively. Moreover, the hsa-miR-134-5p regulated the SHH and TFAP2A gene expression. LINC02035 and C3orf35 were also introduced as important lncRNAs that may involve in competitive endogenous RNA interaction with the SHH for binding to the hsa-miR-149-3p. Moreover, LINC00319, interacting with the hsa-miR-6775-5p, indirectly regulated the MSX2 expression. We also identified various SNPs in the investigated genes that changed the normal structure and thus the function of their related proteins. This study, for the first time, introduces different new proteins, miRNAs, lncRNAs, and SNPs that may be important for normal odontogenesis and the pathology of oral and dental disorders. 

Keywords

References

Akhoundi F, Parvaneh N, Modjtaba EB. 2016. In silico analysis of deleterious single nucleotide polymorphisms in human BUB1 mitotic checkpoint serine/threonine kinase B gene. Meta Gene 9: 142-150.
Babajko S, de La Dure-Molla M, Jedeon K, Berdal A. 2014. MSX2 in ameloblast cell fate and activity. Front Physiol 5: 510. doi: 10.3389/fphys.2014.00510.
Baby N, Alagappan N, Dheen ST, Sajikumar S. 2020. MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aβ (1-42)-induced model of Alzheimer's disease. Aging Cell 19(1): e13046.
Balic A. 2019. Concise review: cellular and molecular mechanisms regulation of tooth initiation. Stem Cells 37(1): 26-32.
Berdal A, Molla M, Hotton D, Aïoub M, Lézot F, Néfussi JR, Goubin G. 2009. Differential impact of MSX1 and MSX2 homeogenes on mouse maxillofacial skeleton. Cells Tissues Organs 189(1-4): 126-132.
Bhagwat M. 2010. Searching NCBI's dbSNP database. Curr Protoc Bioinform Chapter 1: Unit 1.19.
Chen Z, Gao B, Zhou X. 2012. Expression patterns of histone acetyltransferases p300 and CBP during murine tooth development. In Vitro Cell Dev Biol Anim 48(1): 61-68.
Cunha AS, Vertuan Dos Santos L, Schaffer Pugsley Baratto S, Abbasoglu Z, Gerber JT, Paza A, Küchler EC. 2021. Human permanent tooth sizes are associated with genes encoding oestrogen receptors. J Orthod 48(1): 24-32.
Dashti S, Taheri M, Ghafouri-Fard S. 2020. An in-silico method leads to recognition of hub genes and crucial pathways in survival of patients with breast cancer. Sci Rep 10(1): 1-13.
Griss J, Viteri G, Sidiropoulos K, Nguyen V, Fabregat A, Hermjakob H. 2020. ReactomeGSA - efficient multi-omics comparative pathway analysis. Mol Cell Proteomics 19(12): 2115-2125.
Heffer A, Marquart GD, Aquilina-Beck A, Saleem N, Burgess HA, Dawid IB. 2017. Generation and characterization of Kctd15 mutations in zebrafish. PLoS One 12(12): e0189162.
Hermans F, Hemeryck L, Lambrichts I, Bronckaers A, Vankelecom H. 2021. Intertwined signaling pathways governing tooth development: a give-and-take between canonical Wnt and Shh. Front Cell Dev Biol 9: 758203. doi: 10.3389/fcell.2021.758203.
Hosoya A, Shalehin N, Takebe H, Shimo T, Irie K. 2020. Sonic Hedgehog signaling and tooth development. Int J Mol Sci 21(5): 1578. doi: 10.3390/ijms21051587
Huang B, Takahashi K, Sakata-Goto T, Kiso H, Togo Y, Saito K, Bessho K. 2013. Phenotypes of CCAAT/enhancer-binding protein beta deficiency: hyperdontia and elongated coronoid process. Oral Dis 19(2): 144-150.
Huang X, Xu S, Gao J, Liu F, Yue J, Chen T, Wu B. 2011. miRNA expression profiling identifies DSPP regulators in cultured dental pulp cells. Int J Mol Med 28(4): 659-667.
Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, von Mering C. 2009. STRING 8-a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 37(Database issue): D412-D416.
Jiménez-Farfán D, Guevara J, Zenteno E, Malagón H, Hernández-Guerrero JC. 2005. EGF-R and erbB-2 in murine tooth development after ethanol exposure. Birth Defects Res A Clin Mol Teratol 73(2): 65-71.
Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. 2017. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45(D1): D353-D361.
Kobayashi T, Tomofuji T, Machida T, Yoneda T, Ekuni D, Azuma T, Morita M. 2017. Expression of salivary miR-203a-3p was related with oral health-related quality of life in healthy volunteers. Int J Mol Sci 18(6): 1263. doi: 10.3390/ijms18061263.
Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7): 1073-1081.
Lee DS, Yoon WJ, Cho ES, Kim HJ, Gronostajski RM, Cho MI, Park JC. 2011. Crosstalk between nuclear factor I-C and transforming growth factor-β1 signaling regulates odontoblast differentiation and homeostasis. PLoS One 6(12): e29160.
Levi G, Mantero S, Barbieri O, Cantatore D, Paleari L, Beverdam A, Merlo GR. 2006. Msx1 and Dlx5 act independently in development of craniofacial skeleton, but converge on the regulation of Bmp signaling in palate formation. Mech Dev 123(1): 3-16.
Li J, Feng J, Liu Y, Ho TV, Grimes W, Ho HA. Chai Y. 2015. BMP-SHH signaling network controls epithelial stem cell fate via regulation of its niche in the developing tooth. Dev Cell 33(2): 125-135.
Li J, Parada C, Chai Y. 2017. Cellular and molecular mechanisms of tooth root development. Development 144(3): 374-384.
Liao C, Huang X, Gong Y, Lin Q. 2019. Discovery of core genes in colorectal cancer by weighted gene co-expression network analysis. Oncol Lett 18(3):3137-3149.
Liu CJ, Fu X, Xia M, Zhang Q, Gu Z, Guo AY. 2021. miRNASNP-v3: a comprehensive database for SNPs and disease-related variations in miRNAs and miRNA targets. Nucleic Acids Res 49(D1): D1276-D1281.
Liu Z, Chen T, Bai D, Tian W, Chen Y. 2019. Smad7 regulates dental epithelial proliferation during tooth development. J Dent Res 98(12):1376-1385.
Meng T, Huang Y, Wang S, Zhang H, Dechow PC, Wang X, Lu Y. 2015. Twist1 is essential for tooth morphogenesis and odontoblast differentiation. J Biol Chem 290(49):29593-29602.
Nong Y, Guo Y, Gumpert A, Li Q, Tomlin A, Zhu X, Bolli R. 2021. Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction. Mol Cell Biochem 476(11):4093-4106.
Oshima M, Tsuji T. 2015. Whole tooth regeneration as a future dental treatment. Adv Exp Med Biol 881:255-269.
Otasek D, Morris JH, Bouças J, Pico AR, Demchak B. 2019. Cytoscape Automation: empowering workflow-based network analysis. Genome Biol 20: 185. https://doi.org/10.1186/s13059-019-1758-4.
Pandey S, Dhusia K, Katara P, Singh S, Gautam B. 2020. An in silico analysis of deleterious single nucleotide polymorphisms and molecular dynamics simulation of disease linked mutations in genes responsible for neurodegenerative disorder. J Biomol Struct Dyn 38(14): 4259-4272.
Seppala M, Fraser GJ, Birjandi AA, Xavier GM, Cobourne MT. 2017. Sonic Hedgehog signaling and development of the dentition. J Dev Biol 5(2): 6. doi:10.3390/jdb5020006.
Sticht C, De La Torre C, Parveen A, Gretz N. 2018. miRWalk: An online resource for prediction of microRNA binding sites. PLoS One 13(10): e0206239.
Sun YM, Chen YQ. 2020. Principles and innovative technologies for decrypting noncoding RNAs: from discovery and functional prediction to clinical application. J Hematol Oncol 13(1): 1-27.
Thesleff I. 2018. From understanding tooth development to bioengineering of teeth. Eur J Oral Sci 126 : 67-71.
Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. 2010. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform 11(1): 1-10.
Wang C, Dong L, Wang Y. Jiang Z, Zhang J, Yang G. 2021a. Bioinformatics analysis identified miR-584-5p and key miRNA-mRNA networks involved in the osteogenic differentiation of human periodontal ligament stem cells. Front Genet 12: 750827. doi: 10.3389/fgene.2021.750827.
Wang F, Tao R, Zhao L, Hao XH, Zou Y, Lin Q, Chen S. 2021b. Differential lncRNA/mRNA expression profiling and functional network analyses in bmp2 deletion of mouse dental papilla cells. Front Genet 12: 702540. doi: 10.3389/fgene.2021.702540.
Wang J, Wang Q, Zhao T, Liu X, Bai G, Xin Y, Wei B. 2021c. Expression profile of serum-related exosomal miRNAs from parathyroid tumor. Endocrine 72(1): 239-248.
Woodruff ED, Gutierrez GC, Van Otterloo E, Williams T, Cohn MJ. 2021. Anomalous incisor morphology indicates tissue-specific roles for Tfap2a and Tfap2b in tooth development. Dev Biol 472: 67-74.
Xiao CT, Lai WJ, Zhu WA, Wang H. 2020. MicroRNA derived from circulating exosomes as noninvasive biomarkers for diagnosing renal cell carcinoma. Onco Targets Ther 13: 10765. doi: 10.2147/OTT.S271606.
Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, Ma'ayan A. 2021. Gene set knowledge discovery with Enrichr. Curr Protoc 1(3): e90.
Yao B, Cheng X, Mei X, Qiu J, Zhang B, Wang J, Xiao M. 2022. Profiling long noncoding RNA alterations during the stromal cell-derived factor-1α-induced odontogenic differentiation of human dental pulp stem cells. Arch Oral Biol 137: 105393. doi: 10.1016/j.archoralbio.2022.105393.
Yu W, Sun Z, Sweat Y, Sweat M, Venugopalan SR, Eliason S, Amendt BA. 2020. Pitx2-Sox2-Lef1 interactions specify progenitor oral/dental epithelial cell signaling centers. Development 147(11): dev186023. doi: 10.1242/dev.186023.
Yuan Y, Chai Y. 2019. Regulatory mechanisms of jaw bone and tooth development. Curr Top Dev Biol 133: 91-118.
Zhang X, Wang W, Zhu W, Dong J, Cheng Y, Yin Z, Shen F. 2019. Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. Int J Mol Sci 20(22): 5573. doi: 10.3390/ijms20225573.
Journal of Genetic Resources
Volume 8, Issue 2
2022
Pages 165-177

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