title: CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET.
abstract: Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Clifford
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Patel
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Alison E
authors.initials: AE
authors.lastname: John
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Tatler
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mazengarb
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and alan.knox@nottingham.ac.uk.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Knox
mesh_terms: D000107:Acetylation; D056151:Airway Remodeling / Q000276:immunology; D001249:Asthma / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor; D000092468:Bromodomain Containing Proteins
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D016209:Interleukin-8; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D016601:RNA-Binding Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C545012:CEBPB protein, human; C508606:CXCL8 protein, human; C498143:RELA protein, human
keywords: BET protein; CXCl8; airway smooth muscle; asthma; bromodomain; histone acetylation