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.
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Authors | Ke Ren, Wei Zhang, Xiaoqing Chen, Yingyu Ma, Yue Dai, Yimei Fan, Yayi Hou, Ren Xiang Tan, Erguang Li |
Journal | PLoS pathogens
(PLoS Pathog)
Vol. 12
Issue 10
Pg. e1005950
(Oct 2016)
ISSN: 1553-7374 [Electronic] United States |
PMID | 27764245
(Publication Type: Journal Article)
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Chemical References |
- (+)-JQ1 compound
- Azepines
- BRD4 protein, human
- Cell Cycle Proteins
- Nuclear Proteins
- RNA, Small Interfering
- Transcription Factors
- Triazoles
- Positive Transcriptional Elongation Factor B
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Topics |
- Azepines
(pharmacology)
- Blotting, Western
- Cell Cycle Proteins
- Chromatin Immunoprecipitation
- Epigenesis, Genetic
- Gene Knockdown Techniques
- Herpes Simplex
- Herpesvirus 1, Human
(drug effects)
- Herpesvirus 2, Human
(drug effects)
- Host-Parasite Interactions
(physiology)
- Humans
- Microscopy, Confocal
- Nuclear Proteins
(metabolism)
- Polymerase Chain Reaction
- Positive Transcriptional Elongation Factor B
(metabolism)
- RNA, Small Interfering
- Transcription Factors
(metabolism)
- Transfection
- Triazoles
(pharmacology)
- Virus Replication
(drug effects, physiology)
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