title: An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV-1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4.
abstract: The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV infection. Our data support a model that JQ1 enhances HSV infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV infection, this study demonstrates BRD4 has an essential role in HSV infection.
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.|Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.|Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.|Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.|Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.|Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.|Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
authors.forename: Erguang
authors.identifier: http://orcid.org/0000-0002-3065-1336
authors.initials: E
authors.lastname: Li
mesh_terms: D001381:Azepines / Q000494:pharmacology; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins