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

• Published in: PLoS pathogens Vol. 12; no. 10; p. e1005950
• Main Authors: Ren, Ke, Zhang, Wei, Chen, Xiaoqing, Ma, Yingyu, Dai, Yue, Fan, Yimei, Hou, Yayi, Tan, Ren Xiang, Li, Erguang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2016; Public Library of Science (PLoS)
• Subjects: Academic libraries; Azepines - pharmacology; Biology and life sciences; Biotechnology; Blotting, Western; Care and treatment; Chromatin Immunoprecipitation; Colleges & universities; Deoxyribonucleic acid; DNA; Epigenesis, Genetic; Epigenetics; Funding; Gene expression; Gene Knockdown Techniques; Genetic aspects; Herpes Simplex; Herpesviridae; Herpesvirus 1, Human - drug effects; Herpesvirus 2, Human - drug effects; Herpesvirus infections; Host-Parasite Interactions - physiology; Humans; Infections; Laboratories; Medical schools; Medicine; Medicine and Health Sciences; Microscopy, Confocal; Nuclear Proteins - metabolism; Pathogens; Pharmaceuticals; Polymerase Chain Reaction; Positive Transcriptional Elongation Factor B - metabolism; Proteins; Research and Analysis Methods; Risk factors; RNA, Small Interfering; Transcription Factors - metabolism; Transfection; Triazoles - pharmacology; Virus Replication - drug effects; Virus Replication - physiology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005950

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.