The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition
Epigenetics plays an important role in the priming the dynamic response of airway epithelial cells to infectious and environmental stressors. Here, we examine the epigenetic role of the SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin A4 (SMARCA4) in the epithelial response...
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doaj-a2e4937bfa6645acb514543e2cdf6f912021-03-01T05:53:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.633654633654The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast TransitionXiaofang Xu0Dianhua Qiao1Chenyang Dong2Morgan Mann3Roberto P. Garofalo4Sunduz Keles5Sunduz Keles6Allan R. Brasier7Allan R. Brasier8Department of Internal Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI, United StatesDepartment of Internal Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI, United StatesDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Internal Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI, United StatesDepartment of Pediatrics, University of Texas Medical Branch, Galveston, TX, United StatesDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, United StatesDepartment of Internal Medicine, University of Wisconsin-Madison School of Medicine and Public Health (SMPH), Madison, WI, United StatesInstitute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison, Madison, WI, United StatesEpigenetics plays an important role in the priming the dynamic response of airway epithelial cells to infectious and environmental stressors. Here, we examine the epigenetic role of the SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin A4 (SMARCA4) in the epithelial response to RSV infection. Depletion of SMARCA4 destabilized the abundance of the SMARCE1/ARID1A SWI/SNF subunits, disrupting the innate response and triggering a hybrid epithelial/mesenchymal (E/M) state. Assaying SMARCA4 complex-regulated open chromatin domains by transposase cleavage -next generation sequencing (ATAC-Seq), we observed that the majority of cleavage sites in uninfected cells have reduced chromatin accessibility. Paradoxically, SMARCA4 complex-depleted cells showed enhanced RSV-inducible chromatin opening and gene expression in the EMT pathway genes, MMP9, SNAI1/2, VIM, and CDH2. Focusing on the key MMP9, we observed that SMARCA4 complex depletion reduced basal BRD4 and RNA Polymerase II binding, but enhanced BRD4/Pol II binding in response to RSV infection. In addition, we observed that MMP9 secretion in SMARCA4 complex deficient cells contributes to mesenchymal transition, cellular fusion (syncytia) and subepithelial myofibroblast transition. We conclude the SMARCA4 complex is a transcriptional repressor of epithelial plasticity, whose depletion triggers a hybrid E/M state that affects the dynamic response of the small airway epithelial cell in mucosal remodeling via paracrine MMP9 activity.https://www.frontiersin.org/articles/10.3389/fimmu.2021.633654/fullepithelial mesenchymal transitionmatrix metalloproteinase (MMP)myofibroblast transitionairway remodelingextracellular matrix |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiaofang Xu Dianhua Qiao Chenyang Dong Morgan Mann Roberto P. Garofalo Sunduz Keles Sunduz Keles Allan R. Brasier Allan R. Brasier |
spellingShingle |
Xiaofang Xu Dianhua Qiao Chenyang Dong Morgan Mann Roberto P. Garofalo Sunduz Keles Sunduz Keles Allan R. Brasier Allan R. Brasier The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition Frontiers in Immunology epithelial mesenchymal transition matrix metalloproteinase (MMP) myofibroblast transition airway remodeling extracellular matrix |
author_facet |
Xiaofang Xu Dianhua Qiao Chenyang Dong Morgan Mann Roberto P. Garofalo Sunduz Keles Sunduz Keles Allan R. Brasier Allan R. Brasier |
author_sort |
Xiaofang Xu |
title |
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition |
title_short |
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition |
title_full |
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition |
title_fullStr |
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition |
title_full_unstemmed |
The SWI/SNF-Related, Matrix Associated, Actin-Dependent Regulator of Chromatin A4 Core Complex Represses Respiratory Syncytial Virus-Induced Syncytia Formation and Subepithelial Myofibroblast Transition |
title_sort |
swi/snf-related, matrix associated, actin-dependent regulator of chromatin a4 core complex represses respiratory syncytial virus-induced syncytia formation and subepithelial myofibroblast transition |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-03-01 |
description |
Epigenetics plays an important role in the priming the dynamic response of airway epithelial cells to infectious and environmental stressors. Here, we examine the epigenetic role of the SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin A4 (SMARCA4) in the epithelial response to RSV infection. Depletion of SMARCA4 destabilized the abundance of the SMARCE1/ARID1A SWI/SNF subunits, disrupting the innate response and triggering a hybrid epithelial/mesenchymal (E/M) state. Assaying SMARCA4 complex-regulated open chromatin domains by transposase cleavage -next generation sequencing (ATAC-Seq), we observed that the majority of cleavage sites in uninfected cells have reduced chromatin accessibility. Paradoxically, SMARCA4 complex-depleted cells showed enhanced RSV-inducible chromatin opening and gene expression in the EMT pathway genes, MMP9, SNAI1/2, VIM, and CDH2. Focusing on the key MMP9, we observed that SMARCA4 complex depletion reduced basal BRD4 and RNA Polymerase II binding, but enhanced BRD4/Pol II binding in response to RSV infection. In addition, we observed that MMP9 secretion in SMARCA4 complex deficient cells contributes to mesenchymal transition, cellular fusion (syncytia) and subepithelial myofibroblast transition. We conclude the SMARCA4 complex is a transcriptional repressor of epithelial plasticity, whose depletion triggers a hybrid E/M state that affects the dynamic response of the small airway epithelial cell in mucosal remodeling via paracrine MMP9 activity. |
topic |
epithelial mesenchymal transition matrix metalloproteinase (MMP) myofibroblast transition airway remodeling extracellular matrix |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.633654/full |
work_keys_str_mv |
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