title: BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
abstract: Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
authors.forename: Jinjing
authors.identifier: 0000-0002-0612-8553
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Xiangming
authors.initials: X
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361101, China;
authors.forename: Ruichuan
authors.identifier: 0000-0002-7891-9231
authors.initials: R
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Judith
authors.identifier: 0000-0002-6023-7793
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; and.
authors.forename: Richard M
authors.identifier: 0000-0002-4836-5960
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801; Department of Medical Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801 lfchen@life.illinois.edu.
authors.forename: Lin-Feng
authors.identifier: 0000-0003-1809-1580
authors.initials: LF
authors.lastname: Chen
mesh_terms: D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005756:Gastritis / Q000209:etiology / Q000276:immunology*; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D012333:RNA, Messenger; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins