Wfs1基因敲除小鼠肝脏芯片数据的生物信息学分析
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摘要
目的:通过生物信息学方法分析Wfs1基因敲除小鼠肝脏的基因表达谱芯片,探讨WFS1基因突变的潜在致病机制。方法:从美国国立生物技术信息中心GEO数据库下载基因表达谱芯片数据(GSE55143),利用分析工具GEO2R进行差异表达基因筛选,通过在线富集分析网站进行差异表达基因的GO以及KEGG通路富集分析,并使用STRING数据库及Cytoscape软件构建蛋白质相互作用网络。结果:筛选出198个差异表达基因,其中有96个上调基因,102个下调基因。GO和KEGG富集分析表明差异表达基因主要富集于脂肪酸生物合成和初级胆汁酸生物合成这两条信号通路。蛋白质相互作用网络分析发现26个核心基因。结论:本研究筛选出的差异表达基因及相关富集分析可促进对WFS1基因突变致病机制的进一步理解。
Objective: To explore the potential pathogenesis of WFS1 gene mutation by bioinformatics analysis of hepatic gene expression profile in Wfs1 knockout mouse. Methods: GSE55143 were downloaded from Gene Expression Omnibus database. Differentially expressed genes were obtained using GEO2R. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed for differentially expressed genes by online database. Protein-protein interaction network was established by STRING and visualized by Cytoscape. Results: A total of 198 differentially expressed genes were obtained,including 96 up-regulated genes and 102 down-regulated genes. GO and KEGG analyses showed that differentially expressed genes were significantly enriched in fatty acid biosynthesis and primary bile acid biosynthesis. Twenty-six hub genes were discovered in protein-protein interaction network. Conclusion: Differentially expressed genes and associated enrichment analyses may help to understand the pathogenesis of WFS1 mutation,thus providing potential targets for treatment.
Objective: To explore the potential pathogenesis of WFS1 gene mutation by bioinformatics analysis of hepatic gene expression profile in Wfs1 knockout mouse. Methods: GSE55143 were downloaded from Gene Expression Omnibus database. Differentially expressed genes were obtained using GEO2R. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed for differentially expressed genes by online database. Protein-protein interaction network was established by STRING and visualized by Cytoscape. Results: A total of 198 differentially expressed genes were obtained,including 96 up-regulated genes and 102 down-regulated genes. GO and KEGG analyses showed that differentially expressed genes were significantly enriched in fatty acid biosynthesis and primary bile acid biosynthesis. Twenty-six hub genes were discovered in protein-protein interaction network. Conclusion: Differentially expressed genes and associated enrichment analyses may help to understand the pathogenesis of WFS1 mutation,thus providing potential targets for treatment.
引文
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[2]Strom TM,H9rtnagel K,Hofmann S,et al.Diabetes insipidus,diabetes mellitus,optic atrophy and deafness(DIDMOAD)caused by mutations in a novel gene(wolframin)coding for a predicted transmembrane protein[J].Hum Mol Genet,1998,7(13):2021-2028.
[3]Barrett TG,Bundey SE,Macleod AF.Neurodegeneration and diabetes:UK nationwide study of Wolfram(DID-MOAD)syndrome[J].Lancet,1995,346(8988):1458-1463.
[4]Bansal V,Boehm BO,Darvasi A.Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type2 diabetes in Ashkenazi Jewish individuals[J].Diabetologia,2018,61(10):2180-2188.
[5]Punapart M,Eltermaa M,Oflijan J,et al.Effect of chronic valproic acid treatment on hepatic gene expression profile in wfs1 knockout mouse[J].PPAR Res,2014:349525.
[6]Szklarczyk D,Franceschini A,Wyder S,et al.STRINGv10:protein-protein interaction networks,integrated over the tree of life[J].Nucleic Acids Res,2015,43(Database issue):D447-452.
[7]Shannon P,Markiel A,Ozier O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks[J].Genome Res,2003,13(11):2498-2504.
[8]Toots M,Reimets R,Plaas M,et al.Muscarinic agonist ameliorates insulin secretion in Wfs1-deficient mice[J].Can J Diabetes,2019,43(2):115-120.
[9]Noormets K,Koks S,Muldmaa M,et al.Sex differences in the development of diabetes in mice with deleted wolframin(Wfs1)gene[J].Exp Clin Endocrinol Diabetes,2011,119(5):271-275.
[10]Porosk R,Terasmaa A,Mahlapuu R,et al.Metabolomics of the Wolfram syndrome 1 gene(Wfs1)deficient mice[J].OMICS,2017,21(12):721-732.
[11]Wakil SJ,Abu-Elheiga LA.Fatty acid metabolism:target for metabolic syndrome[J].J Lipid Res,2009,50(Suppl):S138-143.
[12]Havula E,Hietakangas V.Sugar sensing by ChREBP/Mondo-Mlx-new insight into downstream regulatory networks and integration of nutrient-derived signals[J].Curr Opin Cell Biol,2018,51:89-96.
[13]Guinez C,Filhoulaud G,Rayah-Benhamed F,et al.O-Glc NAcylation increases ChREBP protein content and transcriptional activity in the liver[J].Diabetes,2011,60(5):1399-1413.
[14]Krycer JR,Sharpe LJ,Luu W,et al.The Akt-SREBPnexus:cell signaling meets lipid metabolism[J].Trends Endocrinol Metab,2010,21(5):268-276.
[15]Kondo M,Tanabe K,Amo-Shiinoki K,et al.Activation of GLP-1 receptor signalling alleviates cellular stresses and improvesβcell function in a mouse model of Wolfram syndrome[J].Diabetologia,2018,61(10):2189-2201.
[16]Koks S,Soomets U,Paya-Cano JL,et al.Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway[J].Physiol Genomics,2009,37(3):249-259.
[17]Chavez-Talavera O,Tailleux A,Lefebvre P,et al.Bile acid control of metabolism and inflammation in obesity,type 2 diabetes,dyslipidemia,and nonalcoholic fatty liver disease[J].Gastroenterology,2017,152(7):1679-1694.e3.
[18]Li T,Chiang JY.Bile acid signaling in metabolic disease and drug therapy[J].Pharmacol Rev,2014,66(4):948-983.
[19]Hylemon PB,Zhou H,Pandak WM,et al.Bile acids as regulatory molecules[J].J Lipid Res,2009,50(8):1509-1520.
[20]Sonne DP,van Nierop FS,Kulik W,et al.Postprandial plasma concentrations of individual bile acids and FGF-19 in patients with type 2 diabetes[J].J Clin Endocrinol Metab,2016,101(8):3002-3009.
[21]Trauner M,Claudel T,Fickert P,et al.Bile acids as regulators of hepatic lipid and glucose metabolism[J].Dig Dis,2010,28(1):220-224.
[22]Trabelsi MS,Lestavel S,Staels B,et al.Intestinal bile acid receptors are key regulators of glucose homeostasis[J].Proc Nutr Soc,2017,76(3):192-202.
[23]Cheng Z,Liu G,Zhang X,et al.Improvement of glucose metabolism following long-term taurocholic acid gavage in a diabetic rat model[J].Med Sci Monit,2018,24:7206-7212.
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