Abstract:The significant roles of genetic variants in myasthenia gravis (MG) pathogenesis have been demonstrated in many studies, and recently it has been revealed that aberrant level/regulation of microRNAs (miRNAs) might contribute to the initiation and progression of MG. However, the dysfunction of miRNA associated with single nucleotide polymorphisms (miRSNPs) has not been well investigated in MG. In this study, we created a contemporary catalog of 89 MG risk genes via manual literature-mining. Based on this risk g… Show more
“…4 A,B, seven pathways (PI3K-Akt signalling pathway and pathways in cancer, hepatitis B, bladder cancer, colorectal cancer, pancreatic cancer and prostate cancer) and two gene functions (positive regulation of cell proliferation and cytoplasm) were collectively enriched in both gene and miRNA analyses. Among these coenriched pathways, five were associated with cancer, and one was associated with infectious diseases, which is in accordance with our previous findings 15 – 17 . Figure 4 Gene Ontology and KEGG pathway analysis using genes and targets of miRNAs in CFMSN.…”
Myasthenia gravis (MG) is an autoimmune disease and the most common type of neuromuscular disease. Genes and miRNAs associated with MG have been widely studied; however, the molecular mechanisms of transcription factors (TFs) and the relationship among them remain unclear. A TF–miRNA–gene network (TMGN) of MG was constructed by extracting six regulatory pairs (TF–miRNA, miRNA–gene, TF–gene, miRNA–TF, gene–gene and miRNA–miRNA). Then, 3/4/5-node regulatory motifs were detected in the TMGN. Then, the motifs with the highest Z-score, occurring as 3/4/5-node composite feed-forward loops (FFLs), were selected as statistically significant motifs. By merging these motifs together, we constructed a 3/4/5-node composite FFL motif-specific subnetwork (CFMSN). Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MG. In addition, the genes, TFs and miRNAs in the CFMSN were also utilized to identify potential drugs. Five related genes, 3 TFs and 13 miRNAs, were extracted from the CFMSN. As the most important TF in the CFMSN, MYC was inferred to play a critical role in MG. Pathway enrichment analysis showed that the genes and miRNAs in the CFMSN were mainly enriched in pathways related to cancer and infections. Furthermore, 21 drugs were identified through the CFMSN, of which estradiol, estramustine, raloxifene and tamoxifen have the potential to be novel drugs to treat MG. The present study provides MG-related TFs by constructing the CFMSN for further experimental studies and provides a novel perspective for new biomarkers and potential drugs for MG.
“…4 A,B, seven pathways (PI3K-Akt signalling pathway and pathways in cancer, hepatitis B, bladder cancer, colorectal cancer, pancreatic cancer and prostate cancer) and two gene functions (positive regulation of cell proliferation and cytoplasm) were collectively enriched in both gene and miRNA analyses. Among these coenriched pathways, five were associated with cancer, and one was associated with infectious diseases, which is in accordance with our previous findings 15 – 17 . Figure 4 Gene Ontology and KEGG pathway analysis using genes and targets of miRNAs in CFMSN.…”
Myasthenia gravis (MG) is an autoimmune disease and the most common type of neuromuscular disease. Genes and miRNAs associated with MG have been widely studied; however, the molecular mechanisms of transcription factors (TFs) and the relationship among them remain unclear. A TF–miRNA–gene network (TMGN) of MG was constructed by extracting six regulatory pairs (TF–miRNA, miRNA–gene, TF–gene, miRNA–TF, gene–gene and miRNA–miRNA). Then, 3/4/5-node regulatory motifs were detected in the TMGN. Then, the motifs with the highest Z-score, occurring as 3/4/5-node composite feed-forward loops (FFLs), were selected as statistically significant motifs. By merging these motifs together, we constructed a 3/4/5-node composite FFL motif-specific subnetwork (CFMSN). Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MG. In addition, the genes, TFs and miRNAs in the CFMSN were also utilized to identify potential drugs. Five related genes, 3 TFs and 13 miRNAs, were extracted from the CFMSN. As the most important TF in the CFMSN, MYC was inferred to play a critical role in MG. Pathway enrichment analysis showed that the genes and miRNAs in the CFMSN were mainly enriched in pathways related to cancer and infections. Furthermore, 21 drugs were identified through the CFMSN, of which estradiol, estramustine, raloxifene and tamoxifen have the potential to be novel drugs to treat MG. The present study provides MG-related TFs by constructing the CFMSN for further experimental studies and provides a novel perspective for new biomarkers and potential drugs for MG.
“…Human MG risk gene data was acquired using the following two approaches: i) Gene information was obtained by searching certain current databases, including DisGeNET (http://www.disgenet. org/web/DisGeNET/menu) (15) and Online Mendelian Inheritance in Man (http://www.omim.org/) (16); and ii) using the protocols published in our previous studies (6,7), the gene was notably differentially expressed in more than five MG samples using dependable biological laboratorial techniques, and 9,514 items were browsed by manually collecting literature using the terms [myasthenia gravis (MeSH Terms) and English (Language)] and the species 'Homo sapiens' published prior to March 1st, 2017 on the PubMed database (https://www.ncbi. nlm.nih.gov/pubmed); the eligible genes were selected.…”
Section: Methodsmentioning
confidence: 99%
“…However, the majority of previous studies investigating MG risk genes have focused on only one or a few genes in cell lines without global analysis. Searches for a number of MG risk genes were performed in our previous studies (6,7), however, the risk genes identified previously were not sufficiently comprehensive. The global pathway analysis of MG risk genes in the present study may assist in further characterizing the pathogenesis of MG.…”
The significant roles of microRNAs (miRNAs) in the pathogenesis of myasthenia gravis (MG) have been observed in numerous previous studies. The impact of miRNA clusters on immunity has been demonstrated in previous years; however, the regulation of miRNA clusters in MG remains to be elucidated. In the present study, 245 MG risk genes were collected and 99 MG risk pathways enriched by these genes were identified. A catalog of 126 MG risk miRNAs was then created; the MG risk miRNAs were located on each chromosome and a miRNA cluster was defined as a number of miRNAs with a relative distance of <6 kb on the same sub-band, same band, same region and same chromosome. Furthermore, enrichment analyses were performed using the target genes of the MG risk miRNA clusters, and a number of risk pathways of each miRNA clusters were identified. As a result, 15 significant miRNA clusters associated with MG were identified. Additionally, the most significant pathways of the miRNA clusters were identified to be enriched on chromosomes 9, 19 and 22, characterized by immunity, infection and carcinoma, suggesting that the mechanism of MG may be associated with certain abnormalities of miRNA clusters on chromosomes 9, 19 and 22. The present study provides novel insight into a global pathway view of miRNA clusters in the pathogenesis of MG.
“…The species of the risk genes was limited to ' Homo sapiens '. We thoroughly read the 9,474 items returned by our searches and selected MG risk genes that met the following standards oulined in a previous study ( 16 ): i) the gene was presented in at least 5 MG samples (including blood samples and thymic tissue samples); ii) the gene was detected using reliable experimental methods, such as microarrays and RT-PCR; and iii) the gene was significantly differentially expressed (mRNA level or protein level). In addition, we also collected MG risk genes from current public databases, including the Genetic Association Database (GAD) ( 17 ), DisGeNET ( 18 ), Online Mendelian Inheritance in Man (OMIM) ( 19 ) and Functional Disease Ontology Annotation (FunDO) ( 20 ).…”
Myasthenia gravis (MG) is a rare debilitating autoimmune neuromuscular disorder. Many studies have focused on the mechanism and treatment strategies of MG. However, the exact pathogenesis of MG and effective treatment strategies remain unclear. Recent studies have indicated that microRNAs (miRNAs or miRs) can regulate the pathological pathways of MG, suggesting their potential role in novel treatments. In the present study, we created a comprehensive catalog of experimentally confirmed MG risk genes and miRNAs by manually mining published literature and public databases. Based on these genes and miRNAs, we identified 41 MG risk pathways and 105 approved drugs that can affect these pathways. Some important MG-related pathways, such as hsa04060 (cytokine-cytokine receptor interaction) and hsa05200 (pathway in cancer), were found to be regulated by MG risk miRNAs and drugs. Furthermore, we constructed an miRNA-regulated drug-pathway network and identified miRNAs and drugs that synergistically regulate key MG pathways and biological processes. We developed a drug repurposing strategy to identify 25 drug repurposing candidates for MG; several of these drugs, such as rituximab, adalimumab, sunitinib, and muromonab, have the potential to be novel MG treatment drugs. This study provides novel insight into the pathogenesis of MG and potential drug candidates for MG were identified.
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