Bioinformatics analyses of differentially expressed genes associated with spinal cord injury:a microarray-based analysis in a mouse model
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摘要
Gene spectrum analysis has shown that gene expression and signaling pathways change dramatically after spinal cord injury,which may affect the microenvironment of the damaged site.Microarray analysis provides a new opportunity for investigating diagnosis,treatment,and prognosis of spinal cord injury.However,differentially expressed genes are not consistent among studies,and many key genes and signaling pathways have not yet been accurately studied.GSE5296 was retrieved from the Gene Expression Omnibus DataSet.Differentially expressed genes were obtained using R/Bioconductor software(expression changed at least two-fold;P < 0.05).Database for Annotation,Visualization and Integrated Discovery was used for functional annotation of differentially expressed genes and Animal Transcription Factor Database for predicting potential transcription factors.The resulting transcription regulatory protein interaction network was mapped to screen representative genes and investigate their diagnostic and therapeutic value for disease.In total,this study identified 109 genes that were upregulated and 30 that were downregulated at 0.5,4,and 24 hours,and 3,7,and 28 days after spinal cord injury.The number of downregulated genes was smaller than the number of upregulated genes at each time point.Database for Annotation,Visualization and Integrated Discovery analysis found that many inflammation-related pathways were upregulated in injured spinal cord.Additionally,expression levels of these inflammation-related genes were maintained for at least 28 days.Moreover,399 regulation modes and 77 nodes were shown in the protein-protein interaction network of upregulated differentially expressed genes.Among the 10 upregulated differentially expressed genes with the highest degrees of distribution,six genes were transcription factors.Among these transcription factors,ATF3 showed the greatest change.ATF3 was upregulated within 30 minutes,and its expression levels remained high at28 days after spinal cord injury.These key genes screened by bioinformatics tools can be used as biological markers to diagnose diseases and provide a reference for identifying therapeutic targets.
Gene spectrum analysis has shown that gene expression and signaling pathways change dramatically after spinal cord injury,which may affect the microenvironment of the damaged site.Microarray analysis provides a new opportunity for investigating diagnosis,treatment,and prognosis of spinal cord injury.However,differentially expressed genes are not consistent among studies,and many key genes and signaling pathways have not yet been accurately studied.GSE5296 was retrieved from the Gene Expression Omnibus DataSet.Differentially expressed genes were obtained using R/Bioconductor software(expression changed at least two-fold;P < 0.05).Database for Annotation,Visualization and Integrated Discovery was used for functional annotation of differentially expressed genes and Animal Transcription Factor Database for predicting potential transcription factors.The resulting transcription regulatory protein interaction network was mapped to screen representative genes and investigate their diagnostic and therapeutic value for disease.In total,this study identified 109 genes that were upregulated and 30 that were downregulated at 0.5,4,and 24 hours,and 3,7,and 28 days after spinal cord injury.The number of downregulated genes was smaller than the number of upregulated genes at each time point.Database for Annotation,Visualization and Integrated Discovery analysis found that many inflammation-related pathways were upregulated in injured spinal cord.Additionally,expression levels of these inflammation-related genes were maintained for at least 28 days.Moreover,399 regulation modes and 77 nodes were shown in the protein-protein interaction network of upregulated differentially expressed genes.Among the 10 upregulated differentially expressed genes with the highest degrees of distribution,six genes were transcription factors.Among these transcription factors,ATF3 showed the greatest change.ATF3 was upregulated within 30 minutes,and its expression levels remained high at28 days after spinal cord injury.These key genes screened by bioinformatics tools can be used as biological markers to diagnose diseases and provide a reference for identifying therapeutic targets.
Gene spectrum analysis has shown that gene expression and signaling pathways change dramatically after spinal cord injury,which may affect the microenvironment of the damaged site.Microarray analysis provides a new opportunity for investigating diagnosis,treatment,and prognosis of spinal cord injury.However,differentially expressed genes are not consistent among studies,and many key genes and signaling pathways have not yet been accurately studied.GSE5296 was retrieved from the Gene Expression Omnibus DataSet.Differentially expressed genes were obtained using R/Bioconductor software(expression changed at least two-fold;P < 0.05).Database for Annotation,Visualization and Integrated Discovery was used for functional annotation of differentially expressed genes and Animal Transcription Factor Database for predicting potential transcription factors.The resulting transcription regulatory protein interaction network was mapped to screen representative genes and investigate their diagnostic and therapeutic value for disease.In total,this study identified 109 genes that were upregulated and 30 that were downregulated at 0.5,4,and 24 hours,and 3,7,and 28 days after spinal cord injury.The number of downregulated genes was smaller than the number of upregulated genes at each time point.Database for Annotation,Visualization and Integrated Discovery analysis found that many inflammation-related pathways were upregulated in injured spinal cord.Additionally,expression levels of these inflammation-related genes were maintained for at least 28 days.Moreover,399 regulation modes and 77 nodes were shown in the protein-protein interaction network of upregulated differentially expressed genes.Among the 10 upregulated differentially expressed genes with the highest degrees of distribution,six genes were transcription factors.Among these transcription factors,ATF3 showed the greatest change.ATF3 was upregulated within 30 minutes,and its expression levels remained high at28 days after spinal cord injury.These key genes screened by bioinformatics tools can be used as biological markers to diagnose diseases and provide a reference for identifying therapeutic targets.
引文
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Bar J,Hasim MS,Baghai T,Niknejad N,Perkins TJ,Stewart DJ,Sekhon HS,Villeneuve PJ,Dimitroulakos J(2016)Induction of activating transcription factor 3 is associated with cisplatin responsiveness in non-small cell lung carcinoma cells.Neoplasia 18:525-535.
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Bastien D,Bellver Landete V,Lessard M,Vallieres N,Champagne M,Takashima A,Tremblay Mè,Doyon Y,Lacroix S(2015)IL-1alpha gene deletion protects oligodendrocytes after spinal cord injury through upregulation of the survival factor Tox3.J Neurosci35:10715-10730.
Boespflug ND,Kumar S,McAlees JW,Phelan JD,Grimes HL,Hoebe K,Hai T,Filippi MD,Karp CL(2014)ATF3 is a novel regulator of mouse neutrophil migration.Blood 123:2084-2093.
Byrnes KR,Washington PM,Knoblach SM,Hoffman E,Faden AI(2011)Delayed inflammatory mRNA and protein expression after spinal cord injury.J Neuroinflammation 8:130.
Carlson SL,Parrish ME,Springer JE,Doty K,Dossett L(1998)Acute inflammatory response in spinal cord following impact injury.Exp Neurol 151:77-88.
Courtine G,van den Brand R,Musienko P(2011)Spinal cord injury:time to move.Lancet 377:1896-1898.
Di Giovanni S,Knoblach SM,Brandoli C,Aden SA,Hoffman EP,Faden AI(2003)Gene profiling in spinal cord injury shows role of cell cycle in neuronal death.Ann Neurol 53:454-468.
Duran RC,Yan H,Zheng Y,Huang X,Grill R,Kim DH,Cao Q,Wu JQ(2017)The systematic analysis of coding and long non-coding RNAs in the sub-chronic and chronic stages of spinal cord injury.Sci Rep7:41008.
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Ghasemlou N,Lopez-Vales R,Lachance C,Thuraisingam T,Gaestel M,Radzioch D,David S(2010)Mitogen-activated protein kinase-activated protein kinase 2(MK2)contributes to secondary damage after spinal cord injury.J Neurosci 30:13750-13759.
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Greenhalgh AD,David S(2014)Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death.J Neurosci 34:6316-6322.
Gregory Alvord W,Roayaei JA,Quinones OA,Schneider KT(2007)Amicroarray analysis for differential gene expression in the soybean genome using Bioconductor and R.Brief Bioinform 8:415-431.
Guerrero AR,Uchida K,Nakajima H,Watanabe S,Nakamura M,Johnson WE,Baba H(2012)Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.J Neuroinflammation 9:40.
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He Z,Jin Y(2016)Intrinsic control of axon regeneration.Neuron90:437-451.
Herrmann JE,Imura T,Song B,Qi J,Ao Y,Nguyen TK,Korsak RA,Takeda K,Akira S,Sofroniew MV(2008)STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury.J Neurosci 28:7231-7243.
Huang CY,Chen JJ,Wu JS,Tsai HD,Lin H,Yan YT,Hsu CY,Ho YS,Lin TN(2015)Novel link of anti-apoptotic ATF3 with pro-apoptotic CTMP in the ischemic brain.Mol Neurobiol 51:543-557.
Huang da W,Sherman BT,Lempicki RA(2009)Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat Protoc 4:44-57.
Iezaki T,Ozaki K,Fukasawa K,Inoue M,Kitajima S,Muneta T,Takeda S,Fujita H,Onishi Y,Horie T,Yoneda Y,Takarada T,Hinoi E(2016)ATF3 deficiency in chondrocytes alleviates osteoarthritis development.J Pathol 239:426-437.
Jain NB,Ayers GD,Peterson EN,Harris MB,Morse L,O’Connor KC,Garshick E(2015)Traumatic spinal cord injury in the United States,1993-2012.JAMA 313:2236-2243.
Kaitu’u-Lino TJ,Brownfoot FC,Hastie R,Chand A,Cannon P,Deo M,Tuohey L,Whitehead C,Hannan NJ,Tong S(2017)Activating transcription factor 3 is reduced in preeclamptic placentas and negatively regulates sFlt-1(Soluble fms-Like Tyrosine Kinase 1),soluble Endoglin,and proinflammatory cytokines in placenta.Hypertension70:1014-1024.
Kim DE,Procopio MG,Ghosh S,Jo SH,Goruppi S,Magliozzi F,Bordignon P,Neel V,Angelino P,Dotto GP(2017)Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.J Exp Med 214:2349-2368.
Koh IU,Lim JH,Joe MK,Kim WH,Jung MH,Yoon JB,Song J(2010)AdipoR2 is transcriptionally regulated by ER stress-inducible ATF3in HepG2 human hepatocyte cells.FEBS J 277:2304-2317.
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Lai PF,Cheng CF,Lin H,Tseng TL,Chen HH,Chen SH(2013)ATF3protects against LPS-induced inflammation in mice via inhibiting HMGB1 expression.Evid Based Complement Alternat Med2013:716481.
Lee-Liu D,Moreno M,Almonacid LI,Tapia VS,Munoz R,von Marees J,Gaete M,Melo F,Larrain J(2014)Genome-wide expression profile of the response to spinal cord injury in Xenopus laevis reveals extensive differences between regenerative and non-regenerative stages.Neural Dev 9:12.
Lin L,Yao Z,Bhuvaneshwar K,Gusev Y,Kallakury B,Yang S,Shetty K,He AR(2014)Transcriptional regulation of STAT3 by SPTBN1 and SMAD3 in HCC through cAMP-response element-binding proteins ATF3 and CREB2.Carcinogenesis 35:2393-2403.
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Barrett T,Wilhite SE,Ledoux P,Evangelista C,Kim IF,Tomashevsky M,Marshall KA,Phillippy KH,Sherman PM,Holko M,Yefanov A,Lee H,Zhang N,Robertson CL,Serova N,Davis S,Soboleva A(2013)NCBI GEO:archive for functional genomics data sets--update.Nucleic Acids Res 41:D991-995.
Bastien D,Bellver Landete V,Lessard M,Vallieres N,Champagne M,Takashima A,Tremblay Mè,Doyon Y,Lacroix S(2015)IL-1alpha gene deletion protects oligodendrocytes after spinal cord injury through upregulation of the survival factor Tox3.J Neurosci35:10715-10730.
Boespflug ND,Kumar S,McAlees JW,Phelan JD,Grimes HL,Hoebe K,Hai T,Filippi MD,Karp CL(2014)ATF3 is a novel regulator of mouse neutrophil migration.Blood 123:2084-2093.
Byrnes KR,Washington PM,Knoblach SM,Hoffman E,Faden AI(2011)Delayed inflammatory mRNA and protein expression after spinal cord injury.J Neuroinflammation 8:130.
Carlson SL,Parrish ME,Springer JE,Doty K,Dossett L(1998)Acute inflammatory response in spinal cord following impact injury.Exp Neurol 151:77-88.
Courtine G,van den Brand R,Musienko P(2011)Spinal cord injury:time to move.Lancet 377:1896-1898.
Di Giovanni S,Knoblach SM,Brandoli C,Aden SA,Hoffman EP,Faden AI(2003)Gene profiling in spinal cord injury shows role of cell cycle in neuronal death.Ann Neurol 53:454-468.
Duran RC,Yan H,Zheng Y,Huang X,Grill R,Kim DH,Cao Q,Wu JQ(2017)The systematic analysis of coding and long non-coding RNAs in the sub-chronic and chronic stages of spinal cord injury.Sci Rep7:41008.
Franceschini A,Szklarczyk D,Frankild S,Kuhn M,Simonovic M,Roth A,Lin J,Minguez P,Bork P,von Mering C,Jensen LJ(2013)STRING v9.1:protein-protein interaction networks,with increased coverage and integration.Nucleic Acids Res 41:D808-815.
Ghasemlou N,Lopez-Vales R,Lachance C,Thuraisingam T,Gaestel M,Radzioch D,David S(2010)Mitogen-activated protein kinase-activated protein kinase 2(MK2)contributes to secondary damage after spinal cord injury.J Neurosci 30:13750-13759.
Gilchrist M,Thorsson V,Li B,Rust AG,Korb M,Roach JC,Kennedy K,Hai T,Bolouri H,Aderem A(2006)Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4.Nature441:173-178.
Greenhalgh AD,David S(2014)Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death.J Neurosci 34:6316-6322.
Gregory Alvord W,Roayaei JA,Quinones OA,Schneider KT(2007)Amicroarray analysis for differential gene expression in the soybean genome using Bioconductor and R.Brief Bioinform 8:415-431.
Guerrero AR,Uchida K,Nakajima H,Watanabe S,Nakamura M,Johnson WE,Baba H(2012)Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.J Neuroinflammation 9:40.
Hashimoto M,Koda M,Ino H,Murakami M,Yamazaki M,Moriya H(2003)Upregulation of osteopontin expression in rat spinal cord microglia after traumatic injury.J Neurotrauma 20:287-296.
Hashimoto M,Koda M,Ino H,Yoshinaga K,Murata A,Yamazaki M,Kojima K,Chiba K,Mori C,Moriya H(2005)Gene expression profiling of cathepsin D,metallothioneins-1 and-2,osteopontin,and tenascin-C in a mouse spinal cord injury model by cDNA microarray analysis.Acta Neuropathol 109:165-180.
He Z,Jin Y(2016)Intrinsic control of axon regeneration.Neuron90:437-451.
Herrmann JE,Imura T,Song B,Qi J,Ao Y,Nguyen TK,Korsak RA,Takeda K,Akira S,Sofroniew MV(2008)STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury.J Neurosci 28:7231-7243.
Huang CY,Chen JJ,Wu JS,Tsai HD,Lin H,Yan YT,Hsu CY,Ho YS,Lin TN(2015)Novel link of anti-apoptotic ATF3 with pro-apoptotic CTMP in the ischemic brain.Mol Neurobiol 51:543-557.
Huang da W,Sherman BT,Lempicki RA(2009)Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat Protoc 4:44-57.
Iezaki T,Ozaki K,Fukasawa K,Inoue M,Kitajima S,Muneta T,Takeda S,Fujita H,Onishi Y,Horie T,Yoneda Y,Takarada T,Hinoi E(2016)ATF3 deficiency in chondrocytes alleviates osteoarthritis development.J Pathol 239:426-437.
Jain NB,Ayers GD,Peterson EN,Harris MB,Morse L,O’Connor KC,Garshick E(2015)Traumatic spinal cord injury in the United States,1993-2012.JAMA 313:2236-2243.
Kaitu’u-Lino TJ,Brownfoot FC,Hastie R,Chand A,Cannon P,Deo M,Tuohey L,Whitehead C,Hannan NJ,Tong S(2017)Activating transcription factor 3 is reduced in preeclamptic placentas and negatively regulates sFlt-1(Soluble fms-Like Tyrosine Kinase 1),soluble Endoglin,and proinflammatory cytokines in placenta.Hypertension70:1014-1024.
Kim DE,Procopio MG,Ghosh S,Jo SH,Goruppi S,Magliozzi F,Bordignon P,Neel V,Angelino P,Dotto GP(2017)Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation.J Exp Med 214:2349-2368.
Koh IU,Lim JH,Joe MK,Kim WH,Jung MH,Yoon JB,Song J(2010)AdipoR2 is transcriptionally regulated by ER stress-inducible ATF3in HepG2 human hepatocyte cells.FEBS J 277:2304-2317.
Kwon BK,Stammers AM,Belanger LM,Bernardo A,Chan D,Bishop CM,Slobogean GP,Zhang H,Umedaly H,Giffin M,Street J,Boyd MC,Paquette SJ,Fisher CG,Dvorak MF(2010)Cerebrospinal fluid inflammatory cytokines and biomarkers of injury severity in acute human spinal cord injury.J Neurotrauma 27:669-682.
Lai PF,Cheng CF,Lin H,Tseng TL,Chen HH,Chen SH(2013)ATF3protects against LPS-induced inflammation in mice via inhibiting HMGB1 expression.Evid Based Complement Alternat Med2013:716481.
Lee-Liu D,Moreno M,Almonacid LI,Tapia VS,Munoz R,von Marees J,Gaete M,Melo F,Larrain J(2014)Genome-wide expression profile of the response to spinal cord injury in Xenopus laevis reveals extensive differences between regenerative and non-regenerative stages.Neural Dev 9:12.
Lin L,Yao Z,Bhuvaneshwar K,Gusev Y,Kallakury B,Yang S,Shetty K,He AR(2014)Transcriptional regulation of STAT3 by SPTBN1 and SMAD3 in HCC through cAMP-response element-binding proteins ATF3 and CREB2.Carcinogenesis 35:2393-2403.
Lind?H,Sk?ld MK,Ochsmann T(2011)Activating transcription factor 3,a useful marker for regenerative response after nerve root injury.Front Neurol 2:30.
Liu XZ,Xu XM,Hu R,Du C,Zhang SX,McDonald JW,Dong HX,Wu YJ,Fan GS,Jacquin MF,Hsu CY,Choi DW(1997)Neuronal and glial apoptosis after traumatic spinal cord injury.J Neurosci 17:5395-5406.
Liu Y,Tachibana T,Dai Y,Kondo E,Fukuoka T,Yamanaka H,Noguchi K(2002)Heme oxygenase-1 expression after spinal cord injury:the induction in activated neutrophils.J Neurotrauma 19:479-490.
Mallano T,Palumbo-Zerr K,Zerr P,Ramming A,Zeller B,Beyer C,Dees C,Huang J,Hai T,Distler O,Schett G,Distler JH(2016)Activating transcription factor 3 regulates canonical TGFbeta signalling in systemic sclerosis.Ann Rheum Dis 75:586-592.
Nesic O,Svrakic NM,Xu GY,McAdoo D,Westlund KN,Hulsebosch CE,Ye Z,Galante A,Soteropoulos P,Tolias P,Young W,Hart RP,Perez-Polo JR(2002)DNA microarray analysis of the contused spinal cord:effect of NMDA receptor inhibition.J Neurosci Res 68:406-423.
Nishimura S,Yasuda A,Iwai H,Takano M,Kobayashi Y,Nori S,Tsuji O,Fujiyoshi K,Ebise H,Toyama Y,Okano H,Nakamura M(2013)Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury.Mol Brain 6:3.
Nordestgaard BG,Nicholls SJ,Langsted A,Ray KK,Tybjaerg-Hansen A(2018)Advances in lipid-lowering therapy through gene-silencing technologies.Nat Rev Cardiol 15:261-272.
Peifer C,Wagner G,Laufer S(2006)New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAPkinase.Curr Top Med Chem 6:113-149.
Qiu J(2009)China spinal cord injury network:changes from within.Lancet Neurol 8:606-607.
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