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Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks.

ABSTRACT: Transcriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA-mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA-mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA-mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA-mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA-mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA-mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA-mRNA regulatory networks might contribute to AUD development.

SUBMITTER: Lim Y

PROVIDER: S-EPMC8487426 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough the study of gene regulation via the action of specific microRNAs (miRNAs) has experienced a boom in recent years, the analysis of genome-wide interaction networks among miRNAs and respective targeted mRNAs has lagged behind. MicroRNAs simultaneously target many transcripts and fine-tune the expression of genes through cooperative/combinatorial targeting. Therefore, they have a large regulatory potential that could widely impact development and progression of diseases, as well as contribute unpredicted collateral effects due to their natural, pathophysiological, or treatment-induced modulation. We support the viewpoint that whole mirnome-transcriptome interaction analysis is required to better understand the mechanisms and potential consequences of miRNA regulation and/or deregulation in relevant biological models. In this study, we tested the hypotheses that ethanol consumption induces changes in miRNA-mRNA interaction networks in the mouse frontal cortex and that some of the changes observed in the mouse are equivalent to changes in similar brain regions from human alcoholics.ResultsmiRNA-mRNA interaction networks responding to ethanol insult were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA). Important pathways (coexpressed modular networks detected by WGCNA) and hub genes central to the neuronal response to ethanol are highlighted, as well as key miRNAs that regulate these processes and therefore represent potential therapeutic targets for treating alcohol addiction. Importantly, we discovered a conserved signature of changing miRNAs between ethanol-treated mice and human alcoholics, which provides a valuable tool for future biomarker/diagnostic studies in humans. We report positively correlated miRNA-mRNA expression networks that suggest an adaptive, targeted miRNA response due to binge ethanol drinking.ConclusionsThis study provides new evidence for the role of miRNA regulation in brain homeostasis and sheds new light on current understanding of the development of alcohol dependence. To our knowledge this is the first report that activated expression of miRNAs correlates with activated expression of mRNAs rather than with mRNA downregulation in an in vivo model. We speculate that early activation of miRNAs designed to limit the effects of alcohol-induced genes may be an essential adaptive response during disease progression.

Project description:Background: Ovarian cancer (OC) is the most lethal malignancy in the female reproductive system. Growing evidences demonstrates that competing endogenous RNA (ceRNA) network play crucial roles in the occurrence and progression of tumors. Therefore, we aimed to explore and identify novel mRNA-miRNA-lncRNA ceRNA networks associated with prognosis of OC. Methods: The differentially expressed gene (DEGs) of four expression profiles datasets (GSE5438, GSE40595, GSE38666 and GSE26712) were collected from Gene Expression Omnibus (GEO) database and analyzed with NetworkAnalyst. Intersection of DEGs were further employed for Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis. Protein-protein interaction (PPI) network and hub genes of DEGs were also identified. The expression levels and survival analysis of the hub genes in OC and their upstream miRNAs and lncRNAs were performed by various bioinformatics databases. More importantly, ceRNA networks were constructed based on mRNA-miRNA-lncRNA in OC. Results: A total of 178 DEGs including 38 upregulated and 140 downregulated genes from intersected DEGs of four expression profiles were identified in OC. Functional enrichment analysis suggested that the commonly DEGs were enriched in regulating enzyme inhibitor activity, glycosaminoglycan and G protein-coupled receptor binding, cell morphogenesis, and involved in pathways including metabolic process, proteoglycans in cancer. Top 10 hub genes with higher connectivity degree were selected for subsequent expression and prognosis analysis. After take expression levels and prognostic roles of hub genes and their upstream miRNAs and lncRNAs in OC into consideration, 2 mRNAs (TACC3 and CXCR4), 2 miRNAs (hsa-miR-425-5p and hsa-miR-146a-5p) and 3 lncRNAs (FUT8-AS1, LINC00665 and LINC01535) were significantly associated with the poor prognosis of OC. The mRNA-miRNA-lncRNA networks (TACC3-hsa-miR-425-5p-FUT8-AS1 and CXCR4-hsa-miR-146a-5p-LINC00665/LINC01535) were eventually constructed in OC based on ceRNA mechanism. Conclusion: We successfully constructed novel ceRNA network associated with the prognosis of ovarian cancer, which may provide a new strategy for early diagnosis and therapeutic intervention of OC.

Project description:Chronic obstructive pulmonary disease (COPD) is characterized by expiratory airflow limitation and symptoms such as shortness of breath. Although many studies have demonstrated dysregulated microRNA (miRNA) and gene (mRNA) expression in the pathogenesis of COPD, how miRNAs and mRNAs systematically interact and contribute to COPD development is still not clear. To gain a deeper understanding of the gene regulatory network underlying COPD pathogenesis, we used Sparse Multiple Canonical Correlation Network (SmCCNet) to integrate whole blood miRNA and RNA-sequencing data from 404 participants in the COPDGene study to identify novel miRNA-mRNA networks associated with COPD-related phenotypes including lung function and emphysema. We hypothesized that phenotype-directed interpretable miRNA-mRNA networks from SmCCNet would assist in the discovery of novel biomarkers that traditional single biomarker discovery methods (such as differential expression) might fail to discover. Additionally, we investigated whether adjusting -omics and clinical phenotypes data for covariates prior to integration would increase the statistical power for network identification. Our study demonstrated that partial covariate adjustment for age, sex, race, and CT scanner model (in the quantitative emphysema networks) improved network identification when compared with no covariate adjustment. However, further adjustment for current smoking status and relative white blood cell (WBC) proportions sometimes weakened the power for identifying lung function and emphysema networks, a phenomenon which may be due to the correlation of smoking status and WBC counts with the COPD-related phenotypes. With partial covariate adjustment, we found six miRNA-mRNA networks associated with COPD-related phenotypes. One network consists of 2 miRNAs and 28 mRNAs which had a 0.33 correlation (p = 5.40E-12) to forced expiratory volume in 1 s (FEV1) percent predicted. We also found a network of 5 miRNAs and 81 mRNAs that had a 0.45 correlation (p = 8.80E-22) to percent emphysema. The miRNA-mRNA networks associated with COPD traits provide a systems view of COPD pathogenesis and complements biomarker identification with individual miRNA or mRNA expression data.

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Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks.

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