Identification of novel gene and pathway targets for human epilepsy treatment

Biological Research - Tập 49 - Trang 1-9 - 2016
Ying Jin1, Chunzhe Zhao1, Lihui Chen1, Xiangyu Liu1, Shuxiao Pan1, Dongsheng Ju1, Jing Ma1, Jinying Li1, Bo Wei2
1Department of Neurology, Jilin Oilfield General Hospital, Songyuan, China
2The Second Division of Neurosurgery, Departments of Neurosurgery, The China-Japan Union Hospital of Jilin University, Changchun, China

Tóm tắt

The aim of this study was to explore epilepsy-related mechanism so as to figure out the possible targets for epilepsy treatment. The gene expression profile dataset GES32534 was downloaded from Gene Expression Omnibus database. We identified the differentially expressed genes (DEGs) by Affy package. Then the DEGs were used to perform gene ontology (GO) and pathway enrichment analyses. Furthermore, a protein–protein interaction (PPI) network was constructed with the DEGs followed by co-expression modules construction and analysis. Total 420 DEGs were screened out, including 214 up-regulated and 206 down-regulated genes. Functional enrichment analysis revealed that down-regulated genes were mainly involved in the process of immunity regulation and biological repairing process while up-regulated genes were closely related to transporter activity. PPI network analysis showed the top ten genes with high degrees were all down-regulated, among which FN1 had the highest degree. The up-regulated and down-regulated DEGs in the PPI network generated two obvious sub-co-expression modules, respectively. In up-co-expression module, SCN3B (sodium channel, voltage gated, type III beta subunit) was enriched in GO:0006814 ~ sodium ion transport. In down-co-expression module, C1QB (complement C1s), C1S (complement component 1, S subcomponent) and CFI (complement factor I) were enriched in GO:0006955 ~ immune response. The immune response and complement system play a major role in the pathogenesis of epilepsy. Additionally, C1QB, C1S, CFI, SCN3B and FN1 may be potential therapeutic targets for epilepsy.

Tài liệu tham khảo

Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J, Forsgren L, French JA, Glynn M. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55:475–82. Lunardi MDS, Souza FPDSD, Xikota JC, Walz R, Lin K. Epilepsy perception amongst education professionals. J Epilepsy Clin Neurophysiol. 2012;18:79–84. Patel AD. Variables associated with emergency department and/or unplanned hospital utilization for children with epilepsy. Epilepsy Behav. 2014;31:172–5. Chen WC, Chen EY, Gebre RZ, Johnson MR, Li N, Vitkovskiy P, Blumenfeld H. Epilepsy and driving: potential impact of transient impaired consciousness. Epilepsy Behav. 2014;30:50–7. McPhee SJ, Lingappa VR, Ganong WF, Lange JD. Pathophysiology of disease: an introduction to clinical medicine. Lange Medical Books/McGraw–Hill; 2000. Eid T, Thomas M, Spencer D, Runden-Pran E, Lai J, Malthankar G, Kim J, Danbolt N, Ottersen O, De Lanerolle N. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet. 2004;363:28–37. Turrin NP, Rivest S. Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis. 2004;16:321–34. Ravizza T, Gagliardi B, Noé F, Boer K, Aronica E, Vezzani A. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis. 2008;29:142–60. Lenburg ME, Liou LS, Gerry NP, Frampton GM, Cohen HT, Christman MF. Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer. 2003;3:31. He K, Xiao W, Lv W. Comprehensive identification of essential pathways and transcription factors related to epilepsy by gene set enrichment analysis on microarray datasets. Int J Mol Med. 2014;34:715–24. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S. A human protein–protein interaction network: a resource for annotating the proteome. Cell. 2005;122:957–68. Fujita A, Sato JR, Rodrigues Lde O, Ferreira CE, Sogayar MC. Evaluating different methods of microarray data normalization. BMC Bioinform. 2006;7:469. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. Da Wei Huang BTS, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4:44–57. Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 2003;4:P3. da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57. Yekutieli D, Benjamini Y. Resampling-based false discovery rate controlling multiple test procedures for correlated test statistics. J Stat Plan Inference. 1999;82:171–96. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C. STRING v9. 1: protein–protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41:D808–15. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7:31–40. Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. 2004;5:575–81. Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS. The cortical innate immune response increases local neuronal excitability leading to seizures. Brain. 2009;132:2478–86. Choi J, Nordli DR, Alden TD, DiPatri A, Laux L, Kelley K, Rosenow J, Schuele SU, Rajaram V, Koh S. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. J Neuroinflammation. 2009;6:38. Vezzani A. Innate immunity and inflammation in temporal lobe epilepsy: new emphasis on the role of complement activation. Epilepsy Curr. 2008;8:75–7. Petry F, Hauptmann G, Goetz J, Grosshans E, Loos M. Molecular basis of a new type of C1q-deficiency associated with a non-functional low molecular weight (LMW) C1q: parallels and differences to other known genetic C1q-defects. Immunopharmacology. 1997;38:189–201. Niesen CE, Xu J, Fan X, Li X, Wheeler CJ, Mamelak AN, Wang C. Transcriptomic profiling of human peritumoral neocortex tissues revealed genes possibly involved in tumor-induced epilepsy. PLoS One. 2013;8:e56077. Aronica E, Ravizza T, Zurolo E, Vezzani A. Astrocyte immune responses in epilepsy. Glia. 2012;60:1258–68. Corry B, Thomas M. Mechanism of ion permeation and selectivity in a voltage gated sodium channel. J Am Chem Soc. 2012;134:1840–6. Jung S, Bullis JB, Lau IH, Jones TD, Warner LN, Poolos NP. Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J Neurosci. 2010;30:6678–88. Baek J-H, Rubinstein M, Scheuer T, Trimmer JS. Reciprocal changes in phosphorylation and methylation of mammalian brain sodium channels in response to seizures. J Biol Chem. 2014;289:15363–73. Frank HY, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol. 2003;4(10):1186. Engvall E, Ruoslahti E. Binding of soluble form of fibroblast surface protein, fibronectin, to collagen. Int J Cancer. 1977;20:1–5. de Rivero Vaccari JP, Dietrich WD, Keane RW. Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. J Cereb Blood Flow Metab. 2014;34:369–75. Müller N, Ackenheil M. Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 1998;22:1–33. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia. 2012;60:1215–26.