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Network and Pathway-Based Analysis of Single-Nucleotide Polymorphism of Mirna in Temporal Lobe Epilepsy

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Network and Pathway-Based Analysis of Single-Nucleotide Polymorphism of Mirna in Temporal Lobe Epilepsy Molecular Neurobiology (2019) 56:7022–7031 https://doi.org/10.1007/s12035-019-1584-4 Network and Pathway-Based Analysis of Single-Nucleotide Polymorphism of miRNA in Temporal Lobe Epilepsy Wenbiao Xiao1 & Yanhao Wu2 & Jianjian Wang3 & Zhaohui Luo1 & Lili Long1 & Na Deng1 & Shangwei Ning4 & Yi Zeng5 & Hongyu Long1 & Bo Xiao1 Received: 18 September 2018 /Accepted: 21 March 2019 /Published online: 9 April 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Temporal lobe epilepsy (TLE) is a complex disease with its pathogenetic mechanism still unclear. Single-nucleotide polymor- phisms (SNPs) of miRNA (miRSNPs) are SNPs located on miRNA genes or target sites of miRNAs, which have been proved to be associated with neuropsychic disease development by interfering with miRNA-mediated regulatory function. In this study, we integrated TLE–related risk genes and risk pathways multi-dimensionally based on public data resources. Furthermore, we systematically screened candidate functional miRSNPs for TLE and constructed a TLE-associated pathway-based miRSNP switching network, which included 92 miRNAs that target 12 TLE risk pathways. Moreover, we dissected thoroughly the correlation between 5 risk genes of 4 risk pathways and TLE development. Additionally, the biological function of several candidate miRSNPs were validated by luciferase reporter assay. In silico approach facilitates to select potential BmiRSNP- miRNA-risk gene-pathway^ axis for experimental validation, which provided new insights into the mechanism of miRSNPs as potential genetic risk factors of TLE. Keywords Temporal lobe epilepsy (TLE) . Risk gene . miRSNP . Pathway . Network Introduction necessitating the evaluation for surgical resection of the epilep- tic focus [2]. As a complex disease, the contribution of genetic Temporal lobe epilepsy (TLE) is the most common form of susceptibility to TLE has been widely studied, and a number of focal epilepsy and often refractory to antiepileptic drugs [1], single-nucleotide polymorphisms (SNPs) have been supposed to be implicated in the pathogenesis mechanism of TLE [3–6]. Although previous studies have provided insights into the sig- Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-019-1584-4) contains supplementary nificant impacts of genetic factors on TLE, the molecular mech- material, which is available to authorized users. anism underlying TLE remains largely indeterminate. A genome-wide association study (GWAS) has become a power- * Hongyu Long ful tool to study the genetic architecture of complex diseases [email protected] and had uncovered tens of thousands of disease-associated * Bo Xiao SNPs [7, 8]. However, the majority of identified SNPs locate [email protected] in the non-coding regions of the genome [9], which remains a challenge to explain the biological significance. 1 Department of Neurology, Xiangya Hospital, Central South MicroRNAs (miRNAs) are a class of endogenous small University, Changsha 410008, China non-coding RNAs (~ 22 nucleotides) that regulate gene ex- 2 Department of Respiratory Medicine, Xiangya Hospital, Central pression at the post-transcriptional level by translational re- South University, Changsha 410008, China pression and/or mRNA deadenylation/decay [10, 11]. 3 Department of Neurology, the Second Affiliated Hospital, Harbin Recently, expression profiling studies in both animal models Medical University, Harbin 150081, China and human epilepsy revealed select changes to brain miRNA 4 College of Bioinformatics Science and Technology, Harbin Medical that mainly impact inflammation, neuronal excitation, and ap- University, Harbin 150081, China optosis, which suggest that miRNAs may regulate certain key 5 Department of Geriatrics, Second Xiangya Hospital, Central South processes broadly altering pathophysiology in epilepsy [12, University, Changsha 410011, China Mol Neurobiol (2019) 56:7022–7031 7023 13]. Moreover, modulating individual miRNA can reduce the abstract was read carefully, and the risk genes which met occurrence of spontaneous seizures and mitigate the attendant the following criteria were recorded: (i) the number of TLE pathological features (neuron loss, gliosis, and rearrangement samples is greater than 5 (mainly includes temporal lobe of mossy fibers) in a TLE model; therefore, miRNAs are novel samples), (ii) there were significant difference between potential therapeutic targets for the treatment of epilepsy [14]. TLE patient samples and the controls in expression levels MiRNAs elicit their functions mainly through sequence- (mRNA level or protein level), (iii) genes in possession of specific binding within the 3′UTR of mRNA transcripts [10, SNPs that prominently associated with TLE patients or 15], so it is believable that miRNA-associated SNP (miRSNP) subgroups. All of the identified risk genes were experimen- could affect miRNA regulation. According to their locations, tally verified by reliable biological methods (PCR, Western miRSNPs have been classified into SNPs within miRNA blotting, et al.) and statistically significant. genes and miRNA target sites [16]. The evidence is mounting that miRSNPs play a vital role in diseases of the central ner- vous system (CNS) including Alzheimer’s disease (AD), Function Enrichment Analysis of TLE Risk Genes Parkinson’s disease (PD), and multiple sclerosis [17]. For in- stance, a functional polymorphism rs1056628 at miR-491-5p To figure out the potential functions of TLE risk genes, we binding site in the 3′UTR of MMP-9 gene confers increased carried out Kyoto Encyclopedia of Genes and Genomes MMP-9 protein expression, which then increased the risk for (KEGG) [23] pathway enrichment analysis by applying func- atherosclerotic cerebral infarction in a Chinese population tional annotation tools in DAVID Bioinformatics Resources [18]. SNP rs662702 of miRNA-328 binding site in the 3′ 6.7 (http://david.abcc.ncifcrf.gov/)[24]. In addition, we UTR of PAX6, which is known to result in increased PAX6 employed DAVID to describe the gene ontology (GO) anno- expression, conferred the increased risk of centrotemporal tation for TLE risk genes [25]. Adjusted P using the spikes of Rolandic epilepsy [19]. A functional rs57095329 Benjamini and Hochberg false discovery rate (FDR) < 0.01 of MIR146A gene is associated with susceptibility to drug- was set as the threshold of significance for KEGG pathway resistant epilepsy and seizure frequency [20]. The miR-124 and GO term. rs531564 polymorphism has no major role in genetic suscep- tibility to mesial TLE in an Italian sample [21], nor does the rs2910164 variant in MIR146A gene [22]. However, to date, MiRNAandmiRNATargetGeneData connecting these miRSNPs to specific genes or to molecular pathways that may be implicated in TLE has not been We downloaded annotation files of human miRNA informa- elaborated. tion from miRBase (http://www.mirbase.org/)[26]. Human In this study, we conducted a bioinformatic genome-wide miRNA target gene data were obtained from 10 miRNA survey of human miRSNPs in miRNA target sites and miRNA target predicting tools, namely RNA22, mirSVR, DIANA- genes themselves and systematically identified candidate microT, PicTar5, RNAhybrid, TargetScan, PITA, functional miRSNPs for TLE based on integrating TLE- MirTarget2, TargetMiner, and miRanda. The target gene related risk genes and risk pathways multi-dimensionally. assemblage of every miRNA was picked out when miRNA Our study helps to unravel miRSNPs that affect the miRNA- target gene pairs were predicted by at least four tools. KEGG mRNA interaction and study the etiology and pathogenesis of pathway enrichment analysis was used in the identification of TLE. In addition, clues for the follow-up studies and function- pathway, in which target genes of individual miRNA were al verification experiments were provided, which contribute to significantly enriched. building the evidence for novel therapeutic targets. MiRSNP Data Materials and Methods The miRSNPs within miRNA target sites were obtained Human TLE Risk Gene Collection from five databases, namely PolymiRTS Database (v.3.0), miRdSNP (v.11.03), MirSNP, miRNASNP (v.2.0), SNP Risk gene data were acquired by browsing the GeneCards effects on microRNA targeting. The miRSNPs within databases (https://www.genecards.org/). Existing studies miRNA genes were obtained from miRvar (v.2.0 Build that focused on genes and TLE were reviewed from 22), miRNASNP (v.2.0), PolymiRTS Database (v.3.0), PubMed (http://www.ncbi.nlm.nih.gov/pubmed)by miRNA-SNiPer. As to the two kinds of miRSNPs, we manually exploring literature published before May 1, screened for the candidate miRSNPs that may potentially 2017 using the terms B(epilepsy, temporal lobe [MeSH impact miRNA-mRNA interactions predicted by at least Terms]) AND English [Language]^.Then,thefulltextor two databases. 7024 Mol Neurobiol (2019) 56:7022–7031 Cumulative Hypergeometric Distribution (candidate SNP, miRNA, and target gene prime were shown in Table S1). All of the constructs were confirmed by Sanger The significant correlations between TLE risk pathways were sequencing. For reporter assays, the 293T cell was co- identified by performing a cumulative hypergeometric test transfected with wild-type (or mutant) reporter plasmid and [27]. The P value was computed using the following formula: miR-Ribo™ mimics (or miR-Ribo™ negative control) using Lipofectamine 3000 (Invitrogen). Luciferase activity was j m−j measured 48 h post-transfection using the dual-luciferase
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