Alternative mRNA Processing of Innate Response Pathways in Respiratory Syncytial Virus (RSV) Infection

Xu, Xiaofang; Mann, Morgan; Qiao, Dianhua; Brasier, Allan R.

doi:10.3390/v13020218

Cited by 13 publications

(14 citation statements)

References 63 publications

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“…RSV replicates in primary human airway epithelial cells, inducing a well-established, time-dependent global genomic response, including both gene activation and repression ( Zhang et al, 2001 ; Xu et al, 2020 ; Xu et al, 2021a ). Consistent with this earlier study, our data indicate that RSV induces dramatic changes in the expression of 11,038 genes (5620 upregulated and 5418 downregulated).…”

Section: Resultsmentioning

confidence: 99%

Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Mann

Qiao

et al. 2021

Front. Mol. Biosci.

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Bromodomain-containing protein 4 plays a central role in coordinating the complex epigenetic component of the innate immune response. Previous studies implicated BRD4 as a component of a chromatin-modifying complex that is dynamically recruited to a network of protective cytokines by binding activated transcription factors, polymerases, and histones to trigger their rapid expression via transcriptional elongation. Our previous study extended our understanding of the airway epithelial BRD4 interactome by identifying over 100 functionally important coactivators and transcription factors, whose association is induced by respiratory syncytial virus (RSV) infection. RSV is an etiological agent of recurrent respiratory tract infections associated with exacerbations of chronic obstructive pulmonary disease. Using a highly selective small-molecule BRD4 inhibitor (ZL0454) developed by us, we extend these findings to identify the gene regulatory network dependent on BRD4 bromodomain (BD) interactions. Human small airway epithelial cells were infected in the absence or presence of ZL0454, and gene expression profiling was performed. A highly reproducible dataset was obtained which indicated that BRD4 mediates both activation and repression of RSV-inducible gene regulatory networks controlling cytokine expression, interferon (IFN) production, and extracellular matrix remodeling. Index genes of functionally significant clusters were validated independently. We discover that BRD4 regulates the expression of its own gene during the innate immune response. Interestingly, BRD4 activates the expression of NFκB/RelA, a coactivator that binds to BRD4 in a BD-dependent manner. We extend this finding to show that BRD4 also regulates other components of its functional interactome, including the Mediator (Med) coactivator complex and the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) subunits. To provide further insight into mechanisms for BRD4 in RSV expression, we mapped 7,845 RSV-inducible Tn5 transposase peaks onto the BRD4-dependent gene bodies. These were located in promoters and introns of cytostructural and extracellular matrix (ECM) formation genes. These data indicate that BRD4 mediates the dynamic response of airway epithelial cells to RNA infection by modulating the expression of its coactivators, controlling the expression of host defense mechanisms and remodeling genes through changes in promoter accessibility.

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Section: Resultsmentioning

confidence: 99%

Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Mann

Qiao

et al. 2021

Front. Mol. Biosci.

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“…It was reported that antiviral pathways and interferon pathways play important roles in COVID-19 patients (38)(39)(40)(41), but the exact mechanism remained unclear. Simultaneously, previous studies have found that APA and AS regulated multiple viral immune processes (7,8,13,(42)(43)(44). However, there is a lack of studies on whether APA affects SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Profiling Reveals Alternative Polyadenylation of Innate Immune-Related mRNA in Patients With COVID-19

Yao

et al. 2021

Front. Immunol.

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The coronavirus disease 2019 (COVID-19) pandemic has caused many deaths worldwide. To date, the mechanism of viral immune escape remains unclear, which is a great obstacle to developing effective clinical treatment. RNA processing mechanisms, including alternative polyadenylation (APA) and alternative splicing (AS), are crucial in the regulation of most human genes in many types of infectious diseases. Because the role of APA and AS in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown, we performed de novo identification of dynamic APA sites using a public dataset of human peripheral blood mononuclear cell (PBMC) RNA-Seq data in COVID-19 patients. We found that genes with APA were enriched in innate immunity -related gene ontology categories such as neutrophil activation, regulation of the MAPK cascade and cytokine production, response to interferon-gamma and the innate immune response. We also reported genome-wide AS events and enriched viral transcription-related categories upon SARS-CoV-2 infection. Interestingly, we found that APA events may give better predictions than AS in COVID-19 patients, suggesting that APA could act as a potential therapeutic target and novel biomarker in those patients. Our study is the first to annotate genes with APA and AS in COVID-19 patients and highlights the roles of APA variation in SARS-CoV-2 infection.

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“…Consequently, the IRF7 protein level is reduced to facilitate viral replication [ 28 ]. Several other IRF7 transcript variants have been reported, and some may be induced by respiratory syncytial virus (RSV) infection [ 29 , 30 ].…”

Section: Alternative Rna Splicing and Its Isoforms In Type I And Iii Ifn Responsesmentioning

confidence: 99%

Role of Alternative Splicing in Regulating Host Response to Viral Infection

Liao

Garcia-Blanco

2021

Cells

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The importance of transcriptional regulation of host genes in innate immunity against viral infection has been widely recognized. More recently, post-transcriptional regulatory mechanisms have gained appreciation as an additional and important layer of regulation to fine-tune host immune responses. Here, we review the functional significance of alternative splicing in innate immune responses to viral infection. We describe how several central components of the Type I and III interferon pathways encode spliced isoforms to regulate IFN activation and function. Additionally, the functional roles of splicing factors and modulators in antiviral immunity are discussed. Lastly, we discuss how cell death pathways are regulated by alternative splicing as well as the potential role of this regulation on host immunity and viral infection. Altogether, these studies highlight the importance of RNA splicing in regulating host–virus interactions and suggest a role in downregulating antiviral innate immunity; this may be critical to prevent pathological inflammation.

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Alternative mRNA Processing of Innate Response Pathways in Respiratory Syncytial Virus (RSV) Infection

Cited by 13 publications

References 63 publications

Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Genome-Wide Profiling Reveals Alternative Polyadenylation of Innate Immune-Related mRNA in Patients With COVID-19

Role of Alternative Splicing in Regulating Host Response to Viral Infection

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