Abstract
DNA demethylation plays an essential role in the reactivation of Epstein-Barr virus (EBV) from latency infection. However, it is unclear how epigenetic modification is initiated in responding to stimuli. Here, we demonstrate that ERK/c-Jun signaling is involved in DNA demethylation of EBV immediate early (IE) gene Zta in response to 12-O-Tetradecanoylphorbol-13-acetate (TPA) stimulation. Remarkably, Ser73 phosphorylation of c-Jun facilitates Zta promoter demethylation and EBV reactivation, whereas knockdown of c-Jun attenuates Zta demethylation and viral reactivation. More importantly, we reveal for the first time that c-Jun interacts with DNA dioxygenase Tet1 and facilitates Tet1 to bind to Zta promoter. The binding of c-Jun and Tet1 to Zta enhances promoter demethylation, resulting in the activation of Zta, the stimulation of BHRF1 (a lytic early gene) and gp350/220 (a lytic late gene), and ultimately the reactivation of EBV. Knockdown of Tet1 attenuates TPA-induced Zta demethylation and EBV reactivation. Thus, TPA activates ERK/c-Jun signaling, which subsequently facilitates Tet1 to bind to Zta promoter, leading to DNA demethylation, gene expression, and EBV reactivation. This study reveals important roles of ERK/c-Jun signaling and Tet1 dioxygenase in epigenetic modification, and provides new insights into the mechanism underlying the regulation of virus latent and lytic infection.
Highlights
DNA demethylation plays an essential role in the reactivation of Epstein-Barr virus (EBV) from latency infection
The γ-herpes viruses immediate early (IE) gene promoter contains a CpG island within 1kb of the transcription start site, which is highly methylated in many epithelial, NK- and B-cell original cancer cell lines and induced promoter demethylation following treatment with TPA and DNA methyltransferase inhibitor azacytidine[2,34,35,36]
As MAPK/ Extracellular signal-related kinase (ERK) signal pathway plays an essential role in expression of Zta and EBV reactivation stimulated by TPA12,13, we speculated that MAPK/ERK signaling may be involvement in the regulation of DNA demethylation
Summary
DNA demethylation plays an essential role in the reactivation of Epstein-Barr virus (EBV) from latency infection. TPA activates ERK/c-Jun signaling, which subsequently facilitates Tet[1] to bind to Zta promoter, leading to DNA demethylation, gene expression, and EBV reactivation. This study reveals important roles of ERK/c-Jun signaling and Tet[1] dioxygenase in epigenetic modification, and provides new insights into the mechanism underlying the regulation of virus latent and lytic infection. The c-Jun directly binds on the Zta promoter and activates its activity[14,15,16,17,18], and the levels of Zta and phosphorylated c-Jun are much higher in EBV-infected AGS gastric carcinoma cells than in EBV-infected HeLa cells[19] It is not clearly whether ERK/c-Jun signaling is required for the epigenetic modification, especially DNA demethylation, to trigger Zta expression and EBV reactivation. The mechanism of demethylation and the role of Tet in EBV reactivation remain largely unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
