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

PLoS Pathogens

Yayi Hou¹  Wei Zhang¹  Yingyu Ma¹  Ren Xiang Tan¹  Xiaoqing Chen²  Erguang Li²  Yimei Fan²  Ke Ren²  Yue Dai³ 

[1] Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China;Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China;The Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China

关键词: Herpes simplex virus;    Library screening;    Viral genes;    Transcriptional control;    Epigenetics;    Herpes simplex virus-1;    HeLa cells;    Viral replication;   

DOI  :  10.1371/journal.ppat.1005950

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY