title: BRD4 mediates NF-κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation.
abstract: Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-κB/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-β challenge in a mouse model. These data provide a detailed mechanism for how activated NF-κB and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas; bitian@utmb.edu.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Bing
authors: 0000-0002-5497-1158
authors: B
authors: Tian
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas; and.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Yingxin
authors: Y
authors: Zhao
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Hong
authors: H
authors: Sun
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Yueqing
authors: Y
authors: Zhang
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Jun
authors: J
authors: Yang
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.|Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas; and.|Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas.
authors: Allan R
authors: AR
authors: Brasier
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D017781:Genes, Immediate-Early; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008168:Lung / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D061805:Transcription Elongation, Genetic / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D042863:Cyclin-Dependent Kinase 9; D016328:NF-kappa B; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse
keywords: BRD4; airway epithelial cells; fibrosis; mesenchymal transition; nuclear factor-κB