title: Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells.
abstract: Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway.
authors.affiliation: Division of Respiratory Medicine, Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB, United Kingdom. Electronic address: pannagos@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Poghosyan
authors.affiliation: Division of Respiratory Medicine, Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB, United Kingdom.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Patel
authors.affiliation: Division of Respiratory Medicine, Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB, United Kingdom.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Clifford
authors.affiliation: Division of Respiratory Medicine, Nottingham Respiratory Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB, United Kingdom. Electronic address: alan.knox@nottingham.ac.uk.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Knox
mesh_terms: D001381:Azepines / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D053583:Interleukin-1beta; D016209:Interleukin-8; D016328:NF-kappa B; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C545012:CEBPB protein, human; C508606:CXCL8 protein, human
keywords: BRD4; CF; CXCL8; Epigenetics