基于mRNA-miRNA相互作用网络研究阿尔茨海默病机理
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摘要
本研究基于表达谱数据系统分析了阿尔茨海默病中的差异表达基因;进一步的GO和KEGG富集分析研究了差异表达基因参与的生物学功能和生物学过程;最后通过mRNA-miRNA相互作用网络,挖掘了阿尔茨海默病中的关键基因和调控机理。研究表明,990个基因在阿尔茨海默病中差异表达(p-value≤0.01,|log FC|≥2),其中332个基因(33.5%)上调,658个基因(66.5%)下调。功能富集(GO)表明,差异基因参与了Regulation of macrophage activation、Myelin sheath和structural constituent of cytoskeleton等功能。KEGG通路富集分析表明,差异基因参与了,Synaptic vesicle cycle、PI3K-Akt signaling pathway、Nicotine addiction、Dopaminergic synapse和Retrograde endocannabinoid signaling等重要的生物学通路。最后,mRNA-miRNA相互作用网络鉴定了在阿尔茨海默病中6个关键的基因,包括TP53INP1、MET、MBNL3、CEBPB、GNAS和SMARCA4,其中TP53INP1和MET在前人的研究中有报道与阿尔茨海默病密切相关,MBNL3、CEBPB、GNAS和SMARCA4是新发现的一些基因。这些基因可能参与了阿尔茨海默病的发生和发展,可以作为其调控位点和药物靶点。
In this study, the differentially expressed genes in Alzheimer's disease(AD) were systematically analyzed based on expression profiles. Further, the biology functions of the DEGs were explored based on GO term and KEGG pathway enrichment analysis. Finally, the critical genes and regulation mechanism of AD were explored based on mRNA-miRNA interaction network. Results showed that 990 genes were differentially expressed in AD with p-value≤0.01 and |log FC|≥2. Among those genes, 332 genes(33.5%) were up-regulated and 658 genes(66.5%)were down-regulated. GO results indicated that differentially expressed genes participated in regulation of macrophage activation,myelin sheath and structural constituent of cytoskeleton and so on. KEGG results showed that differentially expressed genes involved in Synaptic vesicle cycle, PI3 K-Akt signaling pathway, Nicotine addiction, Dopaminergic synapse and Retrograde endocannabinoid signaling and so on. Finally, six critical genes including TP53 INP1, MET, MBNL3, CEBPB, GNAS and SMARCA4 in AD were identified based on mRNA-miRNA interaction network. Among these genes, TP53 INP1 and MET have been reported in previous researches, and MBNL3, CEBPB, GNAS and SMARCA4 were discoveried in this study. The six critical genes probably involved in the occurrence and development of AD and can become the potential drug targets.
In this study, the differentially expressed genes in Alzheimer's disease(AD) were systematically analyzed based on expression profiles. Further, the biology functions of the DEGs were explored based on GO term and KEGG pathway enrichment analysis. Finally, the critical genes and regulation mechanism of AD were explored based on mRNA-miRNA interaction network. Results showed that 990 genes were differentially expressed in AD with p-value≤0.01 and |log FC|≥2. Among those genes, 332 genes(33.5%) were up-regulated and 658 genes(66.5%)were down-regulated. GO results indicated that differentially expressed genes participated in regulation of macrophage activation,myelin sheath and structural constituent of cytoskeleton and so on. KEGG results showed that differentially expressed genes involved in Synaptic vesicle cycle, PI3 K-Akt signaling pathway, Nicotine addiction, Dopaminergic synapse and Retrograde endocannabinoid signaling and so on. Finally, six critical genes including TP53 INP1, MET, MBNL3, CEBPB, GNAS and SMARCA4 in AD were identified based on mRNA-miRNA interaction network. Among these genes, TP53 INP1 and MET have been reported in previous researches, and MBNL3, CEBPB, GNAS and SMARCA4 were discoveried in this study. The six critical genes probably involved in the occurrence and development of AD and can become the potential drug targets.
引文
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Kutmon M.,Kelder T.,Mandaviya P.,Evelo C.T.,and Coort S.L.,2013,Cy Target Linker:a cytoscape app to integrate regulatory interactions in network analysis,PLo S One,8(12):82160
Liang W.S.,Dunckley T.,Beach T.G.,Grover A.,Mastroeni D.,W-alker D.G.,Caselli R.J.,Kukull W.A.,Mc Keel D.,Morris J.C.Hulette C.,Schmechel D.,Alexander G.E.,Reiman E.M.,and Rogers J.,Stephan D.A.,2007,Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain,Physiol.Genomics.,28(3):311-322
Li Z.,Kuang C.,Li G.,Ye L.,Xiong W.,Chen X.B.,Li X.P.,Dai S.Y.,Zhu Y.Q.,Zhang L.,Meng Z.,Tang Y.,and Liu Y.G.2016,Study and analysis of the molecular mechanism of neuroprotective effectof fluoxetine on the nerve cell model of Alzheimer's disease,Jiyinzuxue Yu Yingyong Shengwuxue(Genomics and Applied Biology),35(1):1-5(李曌,况超,李刚,叶柳,熊伟,陈雄斌,李晓朋,戴颂扬,朱殷青,张蕾,孟赞,唐永,刘永刚,2016,氟西汀对阿尔茨海默病神经细胞模型保护作用分子机制的研究分析,基因组学与应用生物学,35(1):1-5)
Maina F.,and Klein R.,1999,Hepatocyte growth factor,a versatile signal for developing neurons,Nat.Neurosci.,2(3):213-217
Mendez M.F.,2012,Early-onset Alzheimer's disease:nonamnestic subtypes and type 2 AD,Arch.Med.Res.,43(8):677-685
Prince M.,Bryce R.,Albanese E.,Wimo A.,Ribeiro W.,and Ferri C.P.,2013,The global prevalence of dementia:a systematic review and metaanalysis,Alzheimers Dement,9(1):63-75
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Seillier M.,Peuget S.,Gayet O.,Gauthier C.,N'Guessan P.Monte M.,Mantua V.,Mecocci P.,Pani L.,Winblad B.,and Dusetti N.J.,2012,TP53INP1,a tumor suppressor,interacts with LC3 and ATG8-family proteins through the LC3-interacting region(LIR)and promotes autophagy-dependent cell death,Cell Death.Differ.,19(9):1525-1535
Sekar S.,Mc Donald J.,Cuyugan L.,Aldrich J.,Kurdoglu A.,Adkins J.,Serrano G.,Beach T.G.,Craig D.W.,Valla J.,Reiman EM.,and Liang W.S.,2015,Alzheimer's disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes,Neurobiol.Aging.,36(2):583-591
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Sharma G.D.,Kakazu A.,and Bazan H.E.,2007,Protein kinase C alpha and epsilon differentially modulate hepatocyte growth factor-induced epithelial proliferation and migration,Exp.Eye Res.,85(2):289-297
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Smoot M.E.,Ono K.,Ruscheinski J.,Wang P.L.,and Ideker T.,2011,Cytoscape 2.8:new features for data integration and network visualization,Bioinformatics,27(3):431-432
Smyth G.K.,'limma:Linear Models for Microarray Data',in Bioinformatics and Computational Biology Solutions Using R and Bioconductor,ed.by Robert Gentleman,Vincent J.Carey,Wolfgang Huber,Rafael A.Irizarry and Sandrine Dudoit(New York,NY:Springer New York,2005,397-420
St George-Hyslop P.H.,Tanzi R.E.,Polinsky R.J.,Haines J.L.,Nee L.,Watkins P.C.,Myers R.H.,Feldman R.G.,Pollen D.,Drachman D.,Growdon J.,Bruni A.,Jean-Francois Foncin,Salmon D.,Frommelt P.,Amaducci L.,Sorbi S.,Piacentini S.,Stewart G.D.,Hobbs W.J.,Conneally P.M.,and Gusella J.F.,1987,The genetic defect causing familial Alzheimer's disease maps on chromosome 21,Science,235(4791):885-890
Tanzi R.E.,Gusella J.F.,Watkins P.C.,Bruns G.A.,St GeorgeHyslop P.,Van Keuren M.L.,Patterson D.,Pagan S.,Kurnit D.M.,and Neve R.L.,1987,Amyloid beta protein gene:c D-NA,m RNA distribution,and genetic linkage near the Alzheimer locus,Science,235(4791):880-884
Van Cauwenberghe C.,Van Broeckhoven C.,and Sleegers K.,2016,The genetic landscape of Alzheimer disease:clinical implications and perspectives,Genet Med,18(5):421-430
Webster J.A.,Gibbs J.R.,Clarke J.,Ray M.,Zhang W.,Holmans P.,Rohrer K.,Zhao A.,Marlowe L.,Kaleem M.,Mc Corquodale D.S.,Cuello C.,Leung D.,Bryden L.,Nath P.,Zismann V.L.,Joshipura K.,Huentelman M.J.,Hu-Lince D.,Coon K.D.,Craig D.W.,Pearson J.V.,Heward C.B.,Reiman E.M.,Stephan D.,Hardy J.,and Myers A.J.,2009,Genetic control of human brain transcript expression in Alzheimer disease,Am.J.Hum.Genet.,84(4):445-458
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Burns A.,and Iliffe S.,2009,Alzheimer's disease,BMJ,338(7692):467-471
Date I.,Takagi N.,Takagi K.,Kago T.,Matsumoto K.,Nakamura T.,and Takeo S.,2004,Hepatocyte growth factor improved learning and memory dysfunction of microsphereembolized rats,J.Neurosci.Res.,78(3):442-453
Dennis G.,Jr.,Sherman B.T.,Hosack D.A.,Yang J.,Gao W.Lane H.C.,and Lempicki R.A.,2003,DAVID:Database for Annotation,Visualization,and Integrated Discovery,Genome Biol.,4(5):3P
Escott-Price V.,Bellenguez C.,Wang L.S.,Choi S.H.,Harold D.,Jones L.,Holmans P.,Gerrish A.,Vedernikov A.,Richards A.,De Stefano A.L.,Lambert J.C.,Ibrahim-Verbaas C.A.Naj A.C.,Sims R.,Jun G.,Bis J.C.,Beecham G.W.,GrenierBoley B.,Russo G.,Thornton-Wells T.A.,Denning N.,Smith A.V.,Chouraki V.,Thomas C.,Ikram M.A.,Zelenika D.Vardarajan B.N.,Kamatani Y.,Lin C.F.,Schmidt H.,Kunkle B.,Dunstan M.L.,Vronskaya M.,Johnson A.D.,Ruiz A.,B-ihoreau M.T.,Reitz C.,Pasquier F.,Hollingworth P.,Hanon O.,Fitzpatrick A.L.,Buxbaum J.D.,Campion D.,Crane P.K.Baldwin C.,Becker T.,Gudnason V.,Cruchaga C.,Craig D.Amin N.,Berr C.,Lopez O.L.,De Jager P.L.,Deramecour V.,Johnston J.A.,Evans D.,Lovestone S.,Letenneur L.,Hernández I.,Rubinsztein D.C.,Eiriksdottir G.,Sleegers K.,Goate A.M.,Fiévet N.,Huentelman M.J.,Gill M.,Brown K.,Kamboh M.I.,Keller L.,Barberger-Gateau P.,Mc Guinness B.,Larson E.B.,Myers A.J.,Dufouil C.,Todd S.,Wallon D.,Love S.,Rogaeva E.,Gallacher J.,George-Hyslop P.S.,Clarimon J.,Lleo A.,Bayer A.,Tsuang D.W.,Yu L.,Tsolaki M.,BossùP.,Spalletta G.,Proitsi P.,Collinge J.,Sorbi S.,Garcia F.S.,Fox N.C.,Hardy J.,Naranjo M.C.,Bosco P.,Clarke R.,Brayne C.,Galimberti D.,Scarpini E.,Bonuccelli U.,Mancuso M.,Siciliano G.,Moebus S.,Mecocci P.,Zompo M.D.,Maier W.,Hampel H.,Pilotto A.,Frank-García A.,Panza F.,Solfrizzi V.,Caffarra P.,Nacmias B.,Perry W.,Mayhaus M.,Lannfelt L.,Hakonarson H.,Pichler S.,Carrasquillo M.M.,Ingelsson M.,Beekly D.,Alvarez V.,Zou F.,Valladares O.,Younkin S.G.,Coto E.,Hamilton-Nelson K.L.,Gu W.,Razquin C.,Pastor P.,Mateo I.,Owen M.J.,Faber K.M.,Jonsson P.V.,Combarros O.,O'Donovan M.C.,Cantwell L.B.,Soininen H.,Blacker D.,Mead S.,Mosley T.H.Jr,Bennett D.A.,Harris T.B.,Fratiglioni L.,Holmes C.,de Bruijn R.F.,Passmore P.,Montine T.J.,Bettens K.,Rotter J.I.,Brice A.,Morgan K.,Foroud T.M.,Kukull W.A.,Hannequin D.,Powell J.F.,Nalls M.A.,Ritchie K.,Lunetta K.L.,Kauwe J.S.,Boerwinkle E.,Riemenschneider M.,Boada M.,Hiltunen M.,Martin E.R.,Schmidt R.,Rujescu D.,Dartigues J.F.,Mayeux R.,Tzourio C.,Hofman A.,N觟then M.M.,Graff C.,Psaty B.M.,Haines J.L.,Lathrop M.,Pericak-Vance M.A.,Launer L.J.,Van Broeckhoven C.,Farrer L.A.,van D-uijn C.M.,Ramirez A.,Seshadri S.,Schellenberg G.D.,Amouyel P.,and Williams J.,2014,Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease,PLo SOne,9(6):e94661
Giusiano S.,Baylot V.,Andrieu C.,Fazli L.,Gleave M.,Iovanna J.L.,Taranger-Charpin C.,Garcia S.,and Rocchi P.,2012,TP53INP1 as new therapeutic target in castration-resistant prostate cancer,Prostate,72(12):1286-1294
Goate A.,2006,Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer's disease,J.Alzheimers Dis.,9(3):341-347
Goldgaber D.,Lerman M.I.,Mc Bride O.W.,Saffiotti U.,and Gajdusek D.C.,1987,Characterization and chromosomal localization of a c DNA encoding brain amyloid of Alzheimer's disease,Science,235(4791):877-880
Hamasaki H.,Honda H.,Suzuki S.O.,Hokama M.,Kiyohara Y.,Nakabeppu Y.,and Iwaki T.,2014,Down-regulation of METin hippocampal neurons of Alzheimer's disease brains,Neuropathology,34(3):284-290
Kutmon M.,Kelder T.,Mandaviya P.,Evelo C.T.,and Coort S.L.,2013,Cy Target Linker:a cytoscape app to integrate regulatory interactions in network analysis,PLo S One,8(12):82160
Liang W.S.,Dunckley T.,Beach T.G.,Grover A.,Mastroeni D.,W-alker D.G.,Caselli R.J.,Kukull W.A.,Mc Keel D.,Morris J.C.Hulette C.,Schmechel D.,Alexander G.E.,Reiman E.M.,and Rogers J.,Stephan D.A.,2007,Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain,Physiol.Genomics.,28(3):311-322
Li Z.,Kuang C.,Li G.,Ye L.,Xiong W.,Chen X.B.,Li X.P.,Dai S.Y.,Zhu Y.Q.,Zhang L.,Meng Z.,Tang Y.,and Liu Y.G.2016,Study and analysis of the molecular mechanism of neuroprotective effectof fluoxetine on the nerve cell model of Alzheimer's disease,Jiyinzuxue Yu Yingyong Shengwuxue(Genomics and Applied Biology),35(1):1-5(李曌,况超,李刚,叶柳,熊伟,陈雄斌,李晓朋,戴颂扬,朱殷青,张蕾,孟赞,唐永,刘永刚,2016,氟西汀对阿尔茨海默病神经细胞模型保护作用分子机制的研究分析,基因组学与应用生物学,35(1):1-5)
Maina F.,and Klein R.,1999,Hepatocyte growth factor,a versatile signal for developing neurons,Nat.Neurosci.,2(3):213-217
Mendez M.F.,2012,Early-onset Alzheimer's disease:nonamnestic subtypes and type 2 AD,Arch.Med.Res.,43(8):677-685
Prince M.,Bryce R.,Albanese E.,Wimo A.,Ribeiro W.,and Ferri C.P.,2013,The global prevalence of dementia:a systematic review and metaanalysis,Alzheimers Dement,9(1):63-75
Schneider L.S.,Mangialasche F.,Andreasen N.,Feldman H.,Giacobini E.,Jones R.,Mantua V.,Mecocci P.,Pani L.,Winblad B.,and Kivipelto M.,2014,Clinical trials and late-stage drug development for Alzheimer's disease:an appraisal from 1984 to 2014,J.Intern.Med.,275(3):251-283
Seillier M.,Peuget S.,Gayet O.,Gauthier C.,N'Guessan P.Monte M.,Mantua V.,Mecocci P.,Pani L.,Winblad B.,and Dusetti N.J.,2012,TP53INP1,a tumor suppressor,interacts with LC3 and ATG8-family proteins through the LC3-interacting region(LIR)and promotes autophagy-dependent cell death,Cell Death.Differ.,19(9):1525-1535
Sekar S.,Mc Donald J.,Cuyugan L.,Aldrich J.,Kurdoglu A.,Adkins J.,Serrano G.,Beach T.G.,Craig D.W.,Valla J.,Reiman EM.,and Liang W.S.,2015,Alzheimer's disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes,Neurobiol.Aging.,36(2):583-591
Seux M.,Peuget S.,Montero M.P.,Siret C.,Rigot V.,Clerc P.Gigoux V.,Pellegrino E.,Pouyet L.,N'Guessan P.,Garcia S.Dufresne M.,Iovanna J.L.,Carrier A.,AndréF.,and Dusett N.J.,2011,TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression,Oncogene,30(27):3049-3061
Sharma G.D.,Kakazu A.,and Bazan H.E.,2007,Protein kinase C alpha and epsilon differentially modulate hepatocyte growth factor-induced epithelial proliferation and migration,Exp.Eye Res.,85(2):289-297
Sharma S.,2010,Hepatocyte growth factor in synaptic plasticity and Alzheimer's disease,Scientific World Journal,10:457-461
Sherrington R.,Rogaev E.I.,Liang Y.,Rogaeva E.A.,Levesque G.,Ikeda M.,Chi H.,Lin C.,Li G.,Holman K.,Tsuda T.,Mar L.,Foncin J.F.,Bruni A.C.,Montesi M.P.,Sorbi S.,Rainero I.,Pinessi L.,Nee L.,Chumakov I.,Pollen D.,Brookes A,Sanseau P.,Polinsky R.J.,Wasco W.,Da Silva H.A.,Haines J.L.,Perkicak-Vance M.A.,Tanzi R.E.,Roses A.D.,Fraser P.E.,Rommens J.M.,and St George-Hyslop P.H.,1995,Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease,Nature,375(6534):754-760
Smoot M.E.,Ono K.,Ruscheinski J.,Wang P.L.,and Ideker T.,2011,Cytoscape 2.8:new features for data integration and network visualization,Bioinformatics,27(3):431-432
Smyth G.K.,'limma:Linear Models for Microarray Data',in Bioinformatics and Computational Biology Solutions Using R and Bioconductor,ed.by Robert Gentleman,Vincent J.Carey,Wolfgang Huber,Rafael A.Irizarry and Sandrine Dudoit(New York,NY:Springer New York,2005,397-420
St George-Hyslop P.H.,Tanzi R.E.,Polinsky R.J.,Haines J.L.,Nee L.,Watkins P.C.,Myers R.H.,Feldman R.G.,Pollen D.,Drachman D.,Growdon J.,Bruni A.,Jean-Francois Foncin,Salmon D.,Frommelt P.,Amaducci L.,Sorbi S.,Piacentini S.,Stewart G.D.,Hobbs W.J.,Conneally P.M.,and Gusella J.F.,1987,The genetic defect causing familial Alzheimer's disease maps on chromosome 21,Science,235(4791):885-890
Tanzi R.E.,Gusella J.F.,Watkins P.C.,Bruns G.A.,St GeorgeHyslop P.,Van Keuren M.L.,Patterson D.,Pagan S.,Kurnit D.M.,and Neve R.L.,1987,Amyloid beta protein gene:c D-NA,m RNA distribution,and genetic linkage near the Alzheimer locus,Science,235(4791):880-884
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