Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia

Tan, Kai Sen; Choi, Hyungwon; Jiang, Xiaoou; Lu, Yin; Seet, Ju Ee; Patzel, Volker; Engelward, Bevin P.; Chow, Vincent T. K.

doi:10.1186/1471-2164-15-587

Cited by 41 publications

(41 citation statements)

References 48 publications

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“…In a murine influenza pneumonia model, miR-200b-5p was predicted to be an important miRNA, connecting regulation of gene functions in repair (43). This suggests that the dysregulation of miR-200b may be a key mediator in pulmonary injury.…”

Section: Discussionmentioning

confidence: 99%

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Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis

Huang¹,

Cong²,

Zhai³

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Pneumonia is a lower respiratory tract infection that causes dramatic mortality worldwide. The present study aimed to investigate the pathogenesis of pneumonia and identify microRNA (miRNA) biomarkers as candidates for targeted therapy. RNA from the peripheral blood plasma of participants with pneumonia (severe, n=9; non-severe, n=9) and controls (n=9) was isolated and paired-end sequencing was performed on an Illumina HiSeq4000 system. Following the processing of raw reads, the sequences were aligned against the Genome Reference Consortium human genome assembly 38 reference genome using Bowtie2 software. Reads per kilobase of transcript per million mapped read values were obtained and the limma software package was used to identify differentially expressed miRNAs (DE-miRs). Then, DE-miR targets were predicted and subjected to enrichment analysis. In addition, a protein-protein interaction (PPI) network of the predicted targets was constructed. This analysis identified 11 key DE-miRs in pneumonia samples, including 6 upregulated miRNAs (including hsa-miR-34a and hsa-miR-455) and 5 downregulated miRNAs (including hsa-let-7f-1). All DE-miRs kept their upregulation/downregulation pattern in the control, non-severe pneumonia and severe pneumonia samples. Predicted target genes of DE-miRs in the subjects with non-severe pneumonia vs. the control and the subjects with severe pneumonia vs. the non-severe pneumonia group were markedly enriched in the adherens junction and Wnt signaling pathways. KALRN, Ras homolog family member A (RHOA), β-catenin (CTNNB1), RNA polymerase II subunit K (POLR2K) and amyloid precursor protein (APP) were determined to encode crucial proteins in the PPI network constructed. KALRN was predicted to be a target of hsa-mir-200b, while RHOA, CTNNB1, POLR2K and APP were predicted targets of hsa-let-7f-1. The results of the present study demonstrated that hsa-let-7f-1 may serve a role in the development of cancer and the Notch signaling pathway. Conversely, hsa-miR-455 may be an inhibitor of pneumonia pathogenesis. Furthermore, hsa-miR-200b might promote pneumonia via targeting KALRN.

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Section: Discussionmentioning

confidence: 99%

“…let-7 acts as an inhibitor during the development of lung cancer, indicating that its downregulation facilitates cell proliferation (27). In mice, let-7b and let-7c have been identified as important miRNAs in the lung restoration at the late stage of influenza pneumonia (27). In human non-small Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis

Huang¹,

Cong²,

Zhai³

et al. 2017

Experimental and Therapeutic Medicine

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“…Further work examined miR-30, let-7, and miR-21 expression changes 15 days after influenza infection. 50 We chose to focus on miR-155 in our study because of the significant amount of interest in this miRNA in fibrosis and also in host defense. Pandemic 2009 H1N1 influenza was shown to induce miR-155 in the lung.…”

Section: Recovery From Influenza Infectionmentioning

confidence: 99%

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

Pociask

Robinson

Chen

et al. 2017

The American Journal of Pathology

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Seasonal and pandemic influenza is a cause of morbidity and mortality worldwide. Most people infected with influenza virus display mild-to-moderate disease phenotypes and recover within a few weeks. Influenza is known to cause persistent alveolitis in animal models; however, little is known about the molecular pathways involved in this phenotype. We challenged C57BL/6 mice with influenza A/PR/8/34 and examined lung pathologic processes and inflammation, as well as transcriptomic and epigenetic changes at 21 to 60 days after infection. Influenza induced persistent parenchymal lung inflammation, alveolar epithelial metaplasia, and epithelial endoplasmic reticulum stress that were evident after the clearance of virus and resolution of morbidity. Influenza infection induced robust changes in the lung transcriptome, including a significant impact on inflammatory and extracellular matrix protein expression. Despite the robust changes in lung gene expression, preceding influenza (21 days) did not exacerbate secondary Staphylococcus aureus infection. Finally, we examined the impact of influenza on miRNA expression in the lung and found an increase in miR-155. miR-155 knockout mice recovered from influenza infection faster than controls and had decreased lung inflammation and endoplasmic reticulum stress. These data illuminate the dynamic molecular changes in the lung in the weeks after influenza infection and characterize the repair process, identifying a novel role for miR-155. (Am J Pathol 2017, 187: 851e863; http://dx

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“…Influenza infection in the lungs causes severe inflammatory damage to the lung through a respiratory outbreak of the innate immune response and the resulting lung injury can lead to other complications or chronic damage if not treated [22]. Zooming into H1N1 influenza A strain, it has been shown to induce acute respiratory distress syndrome (ARDS), pneumonia, alveolar damage, hypoxemia, and massive increase in inflammatory cytokines [18].…”

Section: Resultsmentioning

confidence: 99%

“…Influenza is a very common respiratory pathogen and as such it has been extensively studied to reveal its infection kinetics and pathogenicity [18]. Comprehending the influenza infection phases and especially repair stage will be an enabling step towards preventing these complications by assisting the lung to recover properly [22].…”

Section: Resultsmentioning

confidence: 99%

Detecting Perturbed Subpathways towards Mouse Lung Regeneration Following H1N1 Influenza Infection

et al. 2017

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It has already been established by the systems-level approaches that the future of predictive disease biomarkers will not be sketched by plain lists of genes or proteins or other biological entities but rather integrated entities that consider all underlying component relationships. Towards this orientation, early pathway-based approaches coupled expression data with whole pathway interaction topologies but it was the recent approaches that zoomed into subpathways (local areas of the entire biological pathway) that provided more targeted and context-specific candidate disease biomarkers. Here, we explore the application potential of PerSubs, a graph-based algorithm which identifies differentially activated disease-specific subpathways. PerSubs is applicable both for microarray and RNA-Seq data and utilizes the Kyoto Encyclopedia of Genes and Genomes (KEGG) database as reference for biological pathways. PerSubs operates in two stages: first, identifies differentially expressed genes (or uses any list of disease-related genes) and in second stage, treating each gene of the list as start point, it scans the pathway topology around to build meaningful subpathway topologies. Here, we apply PerSubs to investigate which pathways are perturbed towards mouse lung regeneration following H1N1 influenza infection.

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Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia

Cited by 41 publications

References 48 publications

Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis

Identification of miRNA biomarkers of pneumonia using RNA-sequencing and bioinformatics analysis

Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection

Detecting Perturbed Subpathways towards Mouse Lung Regeneration Following H1N1 Influenza Infection

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