Elucidating the Molecular Mechanism of Ischemic Stroke Using Integrated Analysis of miRNA, mRNA, and lncRNA Expression Profiles.
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ABSTRACT:
SUBMITTER: Sun Y
PROVIDER: S-EPMC8415716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increasing amounts of evidence indicate that noncoding RNAs (ncRNAs) have important roles in various biological processes. Here, miRNA, lncRNA, and mRNA expression profiles were analyzed in human HepG2 and L02 cells using high-throughput technologies. An integrative method was developed to identify possible functional relationships between different RNA molecules. The dominant deregulated miRNAs were prone to be downregulated in tumor cells, and the most abnormal mRNAs and lncRNAs were always upregulated. However, the genome-wide analysis of differentially expressed RNA species did not show significant bias between up- and downregulated populations. miRNA-mRNA interaction was performed based on their regulatory relationships, and miRNA-lncRNA and mRNA-lncRNA interactions were thoroughly surveyed and identified based on their locational distributions and sequence correlations. Aberrantly expressed miRNAs were further analyzed based on their multiple isomiRs. IsomiR repertoires and expression patterns were varied across miRNA loci. Several specific miRNA loci showed differences between tumor and normal cells, especially with respect to abnormally expressed miRNA species. These findings suggest that isomiR repertoires and expression patterns might contribute to tumorigenesis through different biological roles. Systematic and integrative analysis of different RNA molecules with potential cross-talk may make great contributions to the unveiling of the complex mechanisms underlying tumorigenesis.
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Project description:BackgroundLong noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as "microRNA sponges". However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear.Methods3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks.ResultsA total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication.ConclusionsThis study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.
| S-EPMC8015739 | biostudies-literature
Project description:BackgroundStroke is the leading cause of death and disability worldwide, with ischemic stroke (IS) being the most prevalent type. Circular RNAs (circRNAs) are involved in the pathological process of IS and are promising biomarkers for the diagnosis of IS. However, studies focusing on circRNAs acting as microRNAs (miRNAs) sponges in regulating mRNA expression are currently scarce.MethodsIn this study, expression profiles of circRNAs (GSE195442), miRNAs (GSE117064), and mRNAs (GSE58294) from the Gene Expression Omnibus (GEO) database were analyzed. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified by R software. The target miRNAs and target genes were predicted by several bioinformatics methods. Then, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEmRNAs. Subsequently, the protein-protein interaction (PPI) network and the competing endogenous RNA (ceRNA) regulatory network were visualized by Cytoscape software. Finally, we further constructed an immune-related circRNA-miRNA-mRNA regulatory sub-network in IS.ResultsA total of 35 DEcircRNAs, 141 DEmiRNAs, and 356 DEmRNAs were identified. By comprehensive analysis of bioinformatics methods, we constructed a circRNA-miRNA-mRNA regulatory network, including 15 DEcircRNAs, eight DEmiRNAs, and 39 DEmRNAs. FGF9 was identified as an immune-related hub gene. Immune cell analysis indicated a significantly higher level of neutrophils in IS, and the expression of FGF9 was significantly negatively correlated with the level of neutrophils. Eventually, miR-767-5p was predicted as the upstream molecules of FGF9, and circ_0127785 and circ_0075008 were predicted as the upstream circRNAs of miR-767-5p.ConclusionOur study provides novel insights into the molecular mechanisms governing the progression of IS from the perspective of immune-related ceRNA networks.
| S-EPMC9240315 | biostudies-literature
Project description:Stroke known as a neurological disease has significant rates of disability and mortality. Middle cerebral artery occlusion (MCAO) models in rodents is crucial in stroke research to mimic human stroke. Building the mRNA and non-conding RNA network is essential for preventing MCAO-induced ischemic stroke occurrence. Herein, genome-wide mRNA, miRNA, and lncRNA expression profiles among the MCAO group at 3 h, 6 h, and 12 h after surgery and controls using high-throughput RNA sequencing. We detected differentially expressed mRNAs (DE-mRNAs), miRNAs (DE-miRNAs), and lncRNAs (DE-lncRNAs) between the MCAO and control groups. In addition, biological functional analyses were conducted, including GO/KEGG enrichment analysis, and protein-protein interaction analysis (PPI). GO analysis indicated that the DE-mRNAs were mainly enriched in several important biological processes as lipopolysaccharide, inflammatory response, and response to biotic stimulus. The PPI network analysis revealed that the 12 DE-mRNA target proteins showed more than 30° with other proteins, and the top three proteins with the highest node degree were Alb, IL-6, and TNF. In the DE-mRNAs, we found the mRNA of Gp6 and Elane interacting with two miRNAs (novel_miR_879 and novel_miR_528) and two lncRNAs (MSTRG.348134.3 and MSTRG.258402.19). As a result of this study, a new perspective can be gained into the molecular pathophysiology leading to the formation of MCAO. The mRNA-miRNA‒lncRNA regulatory networks play an important role in MCAO-induced ischemic stroke pathogenesis and could be applied to the treatment and prevention of ischemic stroke in the future.
| S-EPMC10203218 | biostudies-literature
Project description:Several studies have investigated miRNA and mRNA co-expression to identify regulatory networks at the transcriptional level. A typical finding of these studies is the presence of both negative and positive miRNA-mRNA correlations. Negative correlations are consistent with the expected, faster degradation of target mRNAs, whereas positive correlations denote the existence of feed-forward regulations mediated by transcription factors. Both mechanisms have been characterized at the molecular level, although comprehensive methods to represent miRNA-mRNA correlations are lacking. At present, genome-wide studies are able to assess the expression of more than 1000 mature miRNAs and more than 35,000 well-characterized human genes. Even if studies are generally restricted to a small subset of genes differentially expressed in specific diseases or experimental conditions, the number of potential correlations remains very high, and needs robust multivariate methods to be conveniently summarized by a small set of data.Nonparametric Kendall correlations were calculated between miRNAs and mRNAs differentially expressed in livers of patients with acute liver failure (ALF) using normal livers as controls. Spurious correlations due to the histopathological composition of samples were removed by partial correlations. Correlations were then transformed into distances and processed by multidimensional scaling (MDS) to map the miRNA and mRNA relationships. These showed: (a) a prominent displacement of miRNA and mRNA clusters in ALF livers, as compared to control livers, indicative of gene expression dysregulation; (b) a clustering of mRNAs consistent with their functional annotations [CYP450, transcription factors, complement, proliferation, HLA class II, monocytes/macrophages, T cells, T-NK cells and B cells], as well as a clustering of miRNAs with the same seed sequence; and (c) a tendency of miRNAs and mRNAs to populate distinct regions of the MDS plot. MDS also allowed to visualize the network of miRNA-mRNA target pairs.Different features of miRNA and mRNA relationships can be represented as thematic maps within the framework of MDS obtained from pairwise correlations. The symmetric distribution of positive and negative correlations between miRNA and mRNA expression suggests that miRNAs are involved in a complex bidirectional molecular network, including, but not limited to, the inhibitory regulation of miRNA targets.
| S-EPMC4603994 | biostudies-literature
Project description:Background: The complicated molecular mechanisms underlying the therapeutic effect of electroacupuncture (EA) on ischemic stroke are still unclear. Recently, more evidence has revealed the essential role of the microRNA (miRNA)-mRNA networks in ischemic stroke. However, a systematic analysis of novel key genes, miRNAs, and miRNA-mRNA networks regulated by EA in ischemic stroke is still absent. Methods: We established a middle cerebral artery occlusion (MCAO) mouse model and performed EA therapy on ischemic stroke mice. Behavior tests and measurement of infarction area were applied to measure the effect of EA treatment. Then, we performed RNA sequencing to analyze differentially expressed genes (DEGs) and functional enrichment between the EA and control groups. In addition, a protein-protein interaction (PPI) network was built, and hub genes were screened by Cytoscape. Upstream miRNAs were predicted by miRTarBase. Then hub genes and predicted miRNAs were verified as key biomarkers by RT-qPCR. Finally, miRNA-mRNA networks were constructed to explore the potential mechanisms of EA in ischemic stroke. Results: Our analysis revealed that EA treatment could significantly alleviate neurological deficits in the affected limbs and reduce infarct area of the MCAO model mice. A total of 174 significant DEGs, including 53 upregulated genes and 121 downregulated genes, were identified between the EA and control groups. Functional enrichment analysis showed that these DEGs were associated with the FOXO signaling pathway, NF-kappa B signaling pathway, T-cell receptor signaling pathway, and other vital pathways. The top 10 genes with the highest degree scores were identified as hub genes based on the degree method, but only seven genes were verified as key genes according to RT-qPCR. Twelve upstream miRNAs were predicted to target the seven key genes. However, only four miRNAs were significantly upregulated and indicated favorable effects of EA treatment. Finally, comprehensive analysis of the results identified the miR-425-5p-Cdk1, mmu-miR-1186b-Prc1, mmu-miR-434-3p-Prc1, and mmu-miR-453-Prc1 miRNA-mRNA networks as key networks that are regulated by EA and linked to ischemic stroke. These networks might mainly take place in neuronal cells regulated by EA in ischemic stroke. Conclusion: In summary, our study identified key DEGs, miRNAs, and miRNA-mRNA regulatory networks that may help to facilitate the understanding of the molecular mechanism underlying the effect of EA treatment on ischemic stroke.
| S-EPMC8461332 | biostudies-literature
Project description:To enhance our understanding of molecular mechanisms and mine novel biomarkers of non-alcoholic fatty liver disease (NAFLD), RNA sequencing was performed to gain hepatic expression profiles of mRNAs and miRNAs in NAFLD and normal rats. Using DESeq with thresholds of a two-fold change and a false discovery rate (FDR) less than 0.05, 336 mRNAs and 21 miRNAs were identified as differentially expressed. Among those, 17 miRNAs (e.g., miR-144-3p, miR-99a-3p, miR-200b-3p, miR-200b-5p, miR-200c-3p, etc.) might serve as novel biomarkers of NAFLD. MiRNA target genes (13565) were predicted by the miRWalk database. Using DAVID 6.8, the intersection (195 genes) of differentially expressed mRNAs and miRNA-predicted target genes were enriched in 47 gene ontology (GO) terms and 28 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Using Cytoscape, pathway interaction and protein-protein interaction (PPI) networks were constructed, and hub genes (e.g., Abcg8, Cyp1a1, Cyp51, Hmgcr, etc.) associated with NAFLD were obtained. Moreover, 673 miRNA-mRNA negative regulatory pairs were obtained, and networks were constructed. Finally, several representative miRNAs and mRNAs were validated by real-time qPCR. In conclusion, potential molecular mechanisms of NAFLD could be inferred from integrated analysis of mRNA and miRNA profiles, which may indicate novel biomarkers of NAFLD.
| S-EPMC5955949 | biostudies-literature
Project description:Prostate cancer, the second most common cancer in men, has been rarely explored by integrating mRNA and miRNA expression profiles. In this study, we combined two mRNA expression datasets and six documented miRNAs to uncover the comprehensive molecular mechanism of prostate cancer. Results showed that a total of 30 genes were significantly differentially expressed in 49 tumor samples by comparing with 22 normal samples. Importantly, all samples from the two datasets can be clearly classified into two groups, tumor group and normal group, based on the selected differentially expressed genes (DEGs). The miRNA-mRNA regulation network indicated that 4 out of 30 DEGs can be regulated by three miRNAs. In addition, prognostic performance validation using in silico databases showed that the DEGs can significantly differentiate between low-risk and high-risk prostate cancer. In summary, multiple biological processes are probably involved in the development and progression of prostate cancer. First, dysregulation of SV2 can regulate transporter and transmembrane transporter activity and then provide the necessary nutrients for tumor cell proliferation. Second, HOXD10 can induce cell proliferation via TCF-4. Finally, dysregulation of CACNA1D can further suppress tumor apoptosis in prostate cancer. The identification of critical genes and valuable biological processes can be useful for the understanding of the molecular mechanism of prostate cancer.
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Project description:Understanding the molecular pattern of fertility is considered as an important step in breeding of different species, and despite the high importance of the fertility, little success has been achieved in dissecting the interactome basis of sheep fertility. However, the complex mechanisms associated with prolificacy in sheep have not been fully understood. Therefore, this study aimed to use competitive endogenous RNA (ceRNA) networks to evaluate this trait to better understand the molecular mechanisms responsible for fertility. A competitive endogenous RNA (ceRNA) network of the corpus luteum was constructed between Romanov and Baluchi sheep breeds with either good or poor genetic merit for prolificacy using whole-transcriptome analysis. First, the main list of lncRNAs, miRNAs, and mRNA related to the corpus luteum that alter with the breed were extracted, then miRNA-mRNA and lncRNA-mRNA interactions were predicted, and the ceRNA network was constructed by integrating these interactions with the other gene regulatory networks and the protein-protein interaction (PPI). A total of 264 mRNAs, 14 lncRNAs, and 34 miRNAs were identified by combining the GO and KEGG enrichment analyses. In total, 44, 7, 7, and 6 mRNAs, lncRNAs, miRNAs, and crucial modules, respectively, were disclosed through clustering for the corpus luteum ceRNA network. All these RNAs involved in biological processes, namely proteolysis, actin cytoskeleton organization, immune system process, cell adhesion, cell differentiation, and lipid metabolic process, have an overexpression pattern (Padj < 0.01). This study increases our understanding of the contribution of different breed transcriptomes to phenotypic fertility differences and constructed a ceRNA network in sheep (Ovis aries) to provide insights into further research on the molecular mechanism and identify new biomarkers for genetic improvement.
| S-EPMC9332185 | biostudies-literature
Project description:BackgroundMany studies on long chain non-coding RNAs (lncRNAs) are published in recent years. But the roles of lncRNAs in aortic dissection (AD) are still unclear and should be further examined. The present work focused on determining the molecular mechanisms underlying lncRNAs regulation in aortic dissection on the basis of the lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network.MethodsThis study collected the lncRNAs (GSE52093), mRNAs (GSE52093) and miRNAs (GSE92427) expression data within human tissue samples with aortic dissection group and normal group based on Gene Expression Omnibus (GEO) database.ResultsThis study identified three differentially expressed lncRNAs (DELs), 19 differentially expressed miRNAs (DEmiRs) and 1046 differentially expressed mRNAs (DEGs) identified regarding aortic dissection. Furthermore, we constructed a lncRNA-miRNA-mRNA network through three lncRNAs (including two with up-regulation and one with down-regulation), five miRNAs (five with up-regulation), as well as 211 mRNAs (including 103 with up-regulation and 108 with down-regulation). Simultaneously, we conducted functional enrichment and pathway analyses on genes within the as-constructed ceRNA network. According to our PPI/ceRNA network and functional enrichment analysis results, four critical genes were found (E2F2, IGF1R, BDNF and PPP2R1B). In addition, E2F2 level was possibly modulated via lncRNA FAM87A-hsa-miR-31-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p. The expression of IGF1R may be regulated by lncRNA FAM87A-hsa-miR-16-5p/hsa-miR-7-5p or lncRNA C9orf106-hsa-miR-7-5p.ConclusionIn conclusion, the ceRNA interaction axis we identified is a potentially critical target for treating AD. Our results shed more lights on the possible pathogenic mechanism in AD using a lncRNA-associated ceRNA network.
| S-EPMC8495997 | biostudies-literature