Construction of potential idiopathic pulmonary fibrosis related microRNA and messenger RNA regulatory network.
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ABSTRACT:
SUBMITTER: Zhang YF
PROVIDER: S-EPMC7929494 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Construction of potential idiopathic pulmonary fibrosis related microRNA and messenger RNA regulatory network.
Zhang Yu-Feng YF Gu Li-Na LN Qi Jia J Xia Qing-Qing QQ Tian Li-Jun LJ Jiang Wei-Long WL Cao Meng-Shu MS
Chinese medical journal 20210105 5
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Project description:ObjectiveTo develop a putative microRNA (miRNA) and messenger RNA (mRNA) regulatory network of Danggui Buxue decoction's (DGBXD) amelioration of idiopathic pulmonary fibrosis (IPF).MethodsThe Gene Expression Omnibus (GEO) database was used to identify differentially expressed miRNAs (DE-miRNAs) and differentially expressed mRNAs (DE-mRNAs). Using miRNet, the predicted target genes of identified DE-miRNAs were estimated, and then the target genes of DE-miRNAs in IPF were comprehensively examined. The Enrichr database was used to conduct functional enrichment and pathway enrichment. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was employed to obtain the target genes of DGBXD as well as active compounds. A putative miRNA-mRNA regulatory network of DGBXD acting on IPF was developed by intersecting the target genes of DGBXD with the DE-miRNA target genes in IPF. A bleomycin-induced mouse model was established and used to perform histopathology as well as real-time quantitative polymerase chain reaction (qRT-PCR) analyses of some miRNA-mRNA pairs.ResultsFourteen upmodulated DE-miRNAs and six downmodulated DE-miRNAs were screened. The downstream target genes of upmodulated and downmodulated DE-miRNAs were predicted. Subsequently, 1160 upmodulated DE-mRNAs and 1427 downmodulated DE-mRNAs were identified. Then, target genes of DE-miRNAs comprising 49 downmodulated and 53 upmodulated target genes were further screened to perform functional enrichment and pathway enrichment analyses. Subsequently, 196 target genes of DGBXD were obtained from TCMSP, with six downregulated target genes and six upregulated target genes of DGBXD acting on IPF being identified. A promising miRNA-mRNA regulatory network of DGBXD acting on IPF was developed in this study. Moreover, mir-493 together with its target gene Olr1 and mir-338 together with Hif1a were further validated by qRT-PCR.ConclusionThis study proposed detailed possible processes of miRNA-mRNA modulatory axis in IPF and constructed a prospective IPF-related miRNA-mRNA modulatory network with the aim of alleviating IPF with DGBXD.
| S-EPMC9064538 | biostudies-literature
Project description:Acute lung injury (ALI) is a life-threatening clinical condition associated with critically ill patients, and the construction of potential microRNA (miRNA) and messenger RNA (mRNA) regulatory networks will help to fully elucidate its underlying molecular mechanisms. First, we screened fifteen upregulated differentially expressed miRNAs (DE-miRNAs) and six downregulated DE-miRNAs from the Gene Expression Omnibus (GEO) database. Then, the predicted target genes of the upregulated and downregulated DE-miRNAs were identified from the miRNet database. Subsequently, differentially expressed mRNAs (DE-mRNAs) were identified from the GEO database and subjected to combined analysis with the predicted DE-miRNA target genes. Eleven target genes of the upregulated DE-miRNAs and one target gene of the downregulated DE-miRNAs were screened out. To further validate the prediction results, we randomly selected a dataset for subsequent analysis and found some accurate potential miRNA-mRNA regulatory axes, including mmu-mir-7b-5p-Gria1, mmu-mir-486a-5p-Shc4 and mmu-mir-486b-5p-Shc4 pairs. Finally, mir-7b and its target gene Gria1 and mir-486b and its target gene Shc4 were further validated in a bleomycin-induced ALI mouse model. We established a potential miRNA-mRNA regulatory network of ALI in mice, which may provide a basis for basic and clinical research on ALI and advance the available treatment options.
| S-EPMC8763866 | biostudies-literature
Project description:Background: Many studies on circular RNAs (circRNAs) have recently been published. However, the function of circRNAs in recurrent implantation failure (RIF) is unknown and remains to be explored. This study aims to determine the regulatory mechanisms of circRNAs in RIF. Methods: Microarray data of RIF circRNA (GSE147442), microRNA (miRNA; GSE71332), and messenger RNA (mRNA; GSE103465) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed circRNA, miRNA, and mRNA. The circRNA-miRNA-mRNA network was constructed by Cytoscape 3.8.0 software, then the protein-protein interaction (PPI) network was constructed by STRING database, and the hub genes were identified by cytoHubba plug-in. The circRNA-miRNA-hub gene regulatory subnetwork was formed to understand the regulatory axis of hub genes in RIF. Finally, the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the hub genes were performed by clusterProfiler package of Rstudio software, and Reactome Functional Interaction (FI) plug-in was used for reactome analysis to comprehensively analyze the mechanism of hub genes in RIF. Results: A total of eight upregulated differentially expressed circRNAs (DECs), five downregulated DECs, 56 downregulated differentially expressed miRNAs (DEmiRs), 104 upregulated DEmiRs, 429 upregulated differentially expressed genes (DEGs), and 1,067 downregulated DEGs were identified regarding RIF. The miRNA response elements of 13 DECs were then predicted. Seven overlapping miRNAs were obtained by intersecting the predicted miRNA and DEmiRs. Then, 56 overlapping mRNAs were obtained by intersecting the predicted target mRNAs of seven miRNAs with 1,496 DEGs. The circRNA-miRNA-mRNA network and PPI network were constructed through six circRNAs, seven miRNAs, and 56 mRNAs; and four hub genes (YWHAZ, JAK2, MYH9, and RAP2C) were identified. The circRNA-miRNA-hub gene regulatory subnetwork with nine regulatory axes was formed in RIF. Functional enrichment analysis and reactome analysis showed that these four hub genes were closely related to the biological functions and pathways of RIF. Conclusion: The results of this study provide further understanding of the potential pathogenesis from the perspective of circRNA-related competitive endogenous RNA network in RIF.
| S-EPMC7924221 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive type of interstitial pneumonia with unknown causes, poor prognosis and no effective therapy available. Circular RNAs (circRNAs), which serve as potential therapeutic targets and diagnostic biomarkers for certain diseases, represent a recent hotspot in the field of RNA research. In the present study, a total of 67 significantly dysregulated circRNAs were identified in the plasma of IPF patients by using a circRNA microarray. Among these circRNAs, 38 were upregulated, whereas 29 were downregulated. Further validation of the results by polymerase chain reaction analysis indicated that Homo sapiens (hsa)_circRNA_100906, hsa_circRNA_102100 and hsa_circRNA_102348 were significantly upregulated, whereas hsa_circRNA_101225, hsa_circRNA_104780 and hsa_circRNA_101242 were downregulated in plasma samples of IPF patients compared with those in samples from healthy controls. The majority of differentially expressed circRNAs were generated from exonic regions. The host genes of the differentially expressed circRNAs were involved in the regulation of the cell cycle, adherens junctions and RNA transport. The competing endogenous RNA (ceRNA) network of the circRNAs/micro(mi)RNAs/mRNAs indicated that circRNA‑protected mRNA participated in transforming growth factor‑β1, hypoxia‑inducible factor‑1, Wnt, Janus kinase, Rho‑associated protein kinase, vascular endothelial growth factor, mitogen‑activated protein kinase, Hedgehog and nuclear factor κB signalling pathways or functioned as biomarkers for pulmonary fibrosis. Furthermore, luciferase reporter assays confirmed that hsa_circRNA_100906 and hsa_circRNA_102348 directly interact with miR‑324‑5p and miR‑630, respectively, which were downregulated in IPF patients. The present study provided a novel avenue for exploring the underlying molecular mechanisms of IPF disease.
| S-EPMC6202105 | biostudies-literature
Project description:BackgroundPatients with non-small cell lung cancer (NSCLC) are diagnosed in advanced stages and with a poor 5-year survival rate. There is a critical need to identify novel biomarkers to improve the therapy and overall prognosis of this disease.MethodsDifferentially expressed genes (DEGs) were identified from three profiles of GSE101586, GSE101684 and GSE112214 using Venn diagrams. hsa_circ_0043256 were validated using quantitative real-time polymerase chain reaction (RT-qPCR). The circular RNA-microRNA-messenger RNA (circRNA-miRNA-mRNA) regulatory network was constructed with Cytoscape 3.7.0. Hub genes were identified with protein interaction (PPI) and validated with the Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas (HPA) databases, and immunohistochemistry. Survival analyses were also performed using a Kaplan-Meier (KM) plotter. The effects of hsa_circ_0043256 on cell proliferation and cell cycles were evaluated by EdU staining and flow cytometry, respectively.Resultshsa_circ_0043256, hsa_circ_0029426 and hsa_circ_0049271 were obtained. Following RT-qPCR validation, hsa_circ_0043256 was selected for further analysis. In addition, functional experiment results indicated that hsa_circ_0043256 could inhibit cell proliferation and cell-cycle progression of NSCLC cells in vitro. Prediction by three online databases and combining with DEGs identified from The Cancer Genome Atlas (TCGA), a network containing one circRNAs, three miRNAs, and 209 mRNAs was developed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated DEGs might be associated with lung cancer onset and progression. A PPI network based on the 209 genes was established, and five hub genes (BIRC5, SHCBP1, CCNA2, SKA3, and GINS1) were determined. Following verification of five hub genes using GEPIA database, HPA database, and immunohistochemistry. High expression of all five hub genes led to poor overall survival.ConclusionOur study constructed a circRNA-miRNA-mRNA network of hsa_circ_0043256. hsa_circ_0043256 may be a potential therapeutic target for lung cancer.
| S-EPMC8720627 | biostudies-literature
Project description:Bleomycin is a common antitumor agent used to treat many different types of malignancies; however, its main side effect is pulmonary fibrosis. The mechanism of bleomycin-induced pulmonary fibrosis (BIPF) has not been fully elucidated. Therefore, to further explore the molecular mechanisms of BIPF, we screened for microRNA (miRNA) and mRNA expression obtained from BIPF samples from the Gene Expression Omnibus database. Subsequently, we identified the differentially expressed miRNAs and genes that overlapped with the differentially expressed miRNAs target genes, predicted by using the miRWalk database selected as a candidate. The candidate genes were visualized based on Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses. A protein-protein interaction network was constructed. Hub differentially expressed genes were selected and corresponding miRNAs to construct a miRNA-mRNA regulation network. Then, we chose three key miRNAs to study their regulatory relationship in bleomycin-induced pulmonary fibrosis. Finally, mouse lung epithelial cells TC-1 and MLE-12 were treated with bleomycin with qPCR to validate the results of three important hub genes and all key miRNAs. And dual-luciferase report experiment was carried out to verify the interaction of mmu-miR-1946a and serpina3n. The results revealed that the imbalance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a pivotal role in the occurrence and development of BIPF. In addition, Serpina3n and mmu-miR-1946a were proved interaction and may be involved in the regulation of the balance between MMP-9 and TIMP-1. The experimental results also verify the analysis. Our findings provide new insights into the key mediators and pathways related to the molecular mechanisms of BIPF.
| S-EPMC8986370 | biostudies-literature
Project description:Objective: The aim of this study was to construct a microRNA (miRNA)-messenger RNA (mRNA)-transcription factor (TF) regulatory network and explore underlying molecular mechanisms, effective biomarkers, and drugs in renal fibrosis (RF). Methods: A total of six datasets were downloaded from Gene Expression Omnibus. "Limma" and "DESeq2" packages in R software and GEO2R were applied to identify the differentially expressed miRNAs and mRNAs (DEmiRNAs and DEmRNAs, respectively). The determination and verification of DEmiRNAs and DEmRNAs were performed through the integrated analysis of datasets from five mouse 7 days of unilateral ureteral obstruction datasets and one human chronic kidney disease dataset and the Human Protein Atlas (http://www.proteinatlas.org). Target mRNAs of DEmiRNAs and TFs were predicted by prediction databases and the iRegulon plugin in Cytoscape, respectively. A protein-protein interaction network was constructed using STRING, Cytoscape v3.9.1, and CytoNCA. Functional enrichment analysis was performed by DIANA-miRPath v3.0 and R package "clusterProfiler." A miRNA-mRNA-TF network was established using Cytoscape. Receiver operating characteristic (ROC) curve analysis was used to examine the diagnostic value of the key hub genes. Finally, the Comparative Toxicogenomics Database and Drug-Gene Interaction database were applied to identify potential drugs. Results: Here, 4 DEmiRNAs and 11 hub genes were determined and confirmed in five mouse datasets, of which Bckdha and Vegfa were further verified in one human dataset and HPA, respectively. Moreover, Bckdha and Vegfa were also predicted by miR-125a-3p and miR-199a-5p, respectively, in humans as in mice. The sequences of miR-125a-3p and miR-199a-5p in mice were identical to those in humans. A total of 6 TFs were predicted to regulate Bckdha and Vegfa across mice and humans; then, a miRNA-mRNA-TF regulatory network was built. Subsequently, ROC curve analysis showed that the area under the curve value of Vegfa was 0.825 (p = 0.002). Finally, enalapril was identified to target Vegfa for RF therapy. Conclusion: Pax2, Pax5, Sp1, Sp2, Sp3, and Sp4 together with Bckdha-dependent miR-125a-3p/Vegfa-dependent miR-199a-5p formed a co-regulatory network enabling Bckdha/Vegfa to be tightly controlled in the underlying pathogenesis of RF across mice and humans. Vegfa could act as a potential novel diagnostic marker and might be targeted by enalapril for RF therapy.
| S-EPMC9705735 | biostudies-literature
Project description:Accumulating evidence indicates an important role for microRNA (miRNA)-messenger RNA (mRNA) regulatory networks in human depression. However, the mechanisms by which these networks act are complex and remain poorly understood. We used data mining to identify differentially expressed miRNAs from GSE81152 and GSE152267 datasets, and differentially expressed mRNAs were identified from the Netherlands Study of Depression and Anxiety, the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program, and the Janssen-Brain Resource Company study. We constructed a miRNA-mRNA regulatory network based on differentially expressed mRNAs that intersected with target genes of differentially expressed miRNAs, and then performed bioinformatics analysis of the network. The key candidate genes were assessed in the prefrontal cortex of chronic social defeat stress (CSDS) depression mice by quantitative real-time polymerase chain reaction (qRT-PCR). Three differentially expressed miRNAs were commonly identified across the two datasets, and 119 intersecting differentially expressed mRNAs were identified. A miRNA-mRNA regulatory network including these three key differentially expressed miRNAs and 119 intersecting differentially expressed mRNAs was constructed. Functional analysis of the intersecting differentially expressed mRNAs revealed that an abnormal inflammatory response characterized by disturbed T-helper cell 17 (Th17) differentiation was the primary altered biological function. qRT-PCR validated the decreased expression of Th17 cell differentiation-related genes, including interleukin (IL)17A, IL21, IL22, and IL1β, and the increased expression of retinoic acid receptor-related orphan receptor gamma-t (RORγt) in CSDS mice, which showed significant depressive- and anxiety-like behaviors. This study indicates that an abnormal inflammatory response characterized by disturbed Th17 cell differentiation is the primary altered biological process in major depressive disorder. Our findings indicate possible biomarkers and treatment targets and provide novel clues to understand the pathogenesis of major depressive disorder.
| S-EPMC9017773 | biostudies-literature
Project description:BackgroundThe transcription factors (TFs)-microRNA (miRNA)-messenger RNA (mRNA) network plays an important role in a variety of diseases. However, the relationship between the TFs-miRNA-mRNA network and idiopathic pulmonary fibrosis (IPF) remains unclear.MethodsThe GSE110147 and GSE53845 datasets from the Gene Expression Omnibus (GEO) database were used to process differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), as well as Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The GSE13316 dataset was used to perform differentially expressed miRNAs (DEMs) analysis and TFs prediction. Finally, a TFs-miRNA-mRNA network related to IPF was constructed, and its function was evaluated by Gene Ontology (GO) and KEGG analyses. Also, 19 TFs in the network were verified by quantitative real time polymerase chain reaction (qRT-PCR).ResultsThrough our analysis, 53 DEMs and 2,630 DEGs were screened. The GSEA results suggested these genes were mainly related to protein digestion and absorption. The WGCNA results showed that these DEGs were divided into eight modules, and the GO and KEGG analyses results of blue module genes showed that these 86 blue module genes were mainly enriched in cilium assembly and cilium organization. Moreover, a TFs-miRNA-mRNA network comprising 25 TFs, 11 miRNAs, and 60 mRNAs was constructed. Ultimately, the functional enrichment analysis showed that the TFs-miRNA-mRNA network was mainly related to the cell cycle and the phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling pathway. Furthermore, experimental verification of the TFs showed that ARNTL, TRIM28, EZH2, BCOR, and ASXL1 were sufficiently up-regulated in the transforming growth factor (TGF)-β1 treatment groups, while BCL6, BHLHE40, FOXA1, and EGR1 were significantly down-regulated.ConclusionsThe novel TFs-miRNA-mRNA network that we constructed could provide new insights into the underlying molecular mechanisms of IPF. ARNTL, TRIM28, EZH2, BCOR, ASXL1, BCL6, BHLHE40, FOXA1, and EGR1 may play important roles in IPF and become effective biomarkers for diagnosis and treatment.
| S-EPMC9929790 | biostudies-literature
Project description:BackgroundCircular RNA (circRNA) is a noncoding RNA that forms a closed-loop structure, and its abnormal expression may cause disease. We aimed to find potential network for circRNA-related competitive endogenous RNA (ceRNA) in atrial fibrillation (AF).MethodsThe circRNA, miRNA, and mRNA expression profiles in the heart tissue from AF patients were retrieved from the Gene Expression Omnibus database and analyzed comprehensively. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified, followed by the establishment of DEcircRNA-DEmiRNA-DEmRNA regulatory network. Functional annotation analysis of host gene of DEcircRNAs and DEmRNAs in ceRNA regulatory network was performed. In vitro experiment and electronic validation were used to validate the expression of DEcircRNAs, DEmiRNAs, and DEmRNAs.ResultsA total of 1611 DEcircRNAs, 51 DEmiRNAs, and 1250 DEmRNAs were identified in AF. The DEcircRNA-DEmiRNA-DEmRNA network contained 62 circRNAs, 14 miRNAs, and 728 mRNAs. Among which, two ceRNA regulatory pairs of hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 were identified. In addition, six miRNA-mRNA regulatory pairs including hsa-miR-34c-5p-INMT, hsa-miR-1253-DDIT4L, hsa-miR-508-5p-SMOC2, hsa-miR-943-ACTA1, hsa-miR-338-3p-WIPI1, and hsa-miR-199a-3p-RAP1GAP2 were also obtained. MTOR was a significantly enriched signaling pathway of host gene of DEcircRNAs. In addition, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy were remarkably enriched signaling pathways of DEmRNAs in DEcircRNA-DEmiRNA-DEmRNA regulatory network. The expression validation of hsa-circRNA-402565, hsa-miR-34c-5p, hsa-miR-188-5p, SPON1, DDIT4L, SMOC2, and WIPI1 was consistent with the integrated analysis.ConclusionWe speculated that hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 interaction pairs may be involved in AF.
| S-EPMC7545447 | biostudies-literature