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Article

Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways

1
Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI 53705, USA
2
Department of Pediatrics, University of Texas Medical Branch, Galveston, TX 77555, USA
3
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
4
Institute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison, Madison, WI 53705, USA
*
Author to whom correspondence should be addressed.
Received: 23 June 2020 / Revised: 17 July 2020 / Accepted: 23 July 2020 / Published: 26 July 2020
(This article belongs to the Special Issue Epigenetics and Viral Infection)
Lower respiratory tract infection (LRTI) with respiratory syncytial virus (RSV) is associated with reduced lung function through unclear mechanisms. In this study, we test the hypothesis that RSV infection induces genomic reprogramming of extracellular matrix remodeling pathways. For this purpose, we sought to identify transcriptionally active open chromatin domains using assay for transposase-accessible-next generation sequencing (ATAC-Seq) in highly differentiated lower airway epithelial cells. High confidence nucleosome-free regions were those predicted independently using two peak-calling algorithms. In uninfected cells, ~12,650 high-confidence open chromatin regions were identified. These mapped to ~8700 gene bodies, whose genes functionally controlled organelle synthesis and Th2 pathways (IL6, TSLP). These latter cytokines are preferentially secreted by RSV-infected bronchiolar cells and linked to mucous production, obstruction, and atopy. By contrast, in RSV infection, we identify ~1700 high confidence open chromatin domains formed in 1120 genes, primarily in introns. These induced chromatin modifications are associated with complex gene expression profiles controlling tyrosine kinase growth factor signaling and extracellular matrix (ECM) secretory pathways. Of these, RSV induces formation of nucleosome-free regions on TGFB1/JUNB//FN1/MMP9 genes and the rate limiting enzyme in the hexosamine biosynthetic pathway (HBP), Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). RSV-induced open chromatin domains are highly enriched in AP1 binding motifs and overlap experimentally determined JUN peaks in GEO ChIP-Seq data sets. Our results provide a topographical map of chromatin accessibility and suggest a growth factor and AP1-dependent mechanism for upregulation of the HBP and ECM remodeling in lower epithelial cells that may be linked to long-term airway remodeling. View Full-Text
Keywords: assay for transposase-accessible next generation sequencing (ATAC-Seq); chromatin remodeling; innate response; hexosamine biosynthetic pathway assay for transposase-accessible next generation sequencing (ATAC-Seq); chromatin remodeling; innate response; hexosamine biosynthetic pathway
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MDPI and ACS Style

Xu, X.; Qiao, D.; Mann, M.; Garofalo, R.P.; Brasier, A.R. Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways. Viruses 2020, 12, 804. https://0-doi-org.brum.beds.ac.uk/10.3390/v12080804

AMA Style

Xu X, Qiao D, Mann M, Garofalo RP, Brasier AR. Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways. Viruses. 2020; 12(8):804. https://0-doi-org.brum.beds.ac.uk/10.3390/v12080804

Chicago/Turabian Style

Xu, Xiaofang, Dianhua Qiao, Morgan Mann, Roberto P. Garofalo, and Allan R. Brasier 2020. "Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways" Viruses 12, no. 8: 804. https://0-doi-org.brum.beds.ac.uk/10.3390/v12080804

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