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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / virology
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Callithrix
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DNA Methylation
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Demethylation / drug effects
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Epigenesis, Genetic*
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Herpesvirus 4, Human / genetics*
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Herpesvirus 4, Human / metabolism
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Host-Pathogen Interactions / genetics
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics*
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mixed Function Oxygenases / antagonists & inhibitors
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Mixed Function Oxygenases / genetics*
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Mixed Function Oxygenases / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Tetradecanoylphorbol Acetate / pharmacology
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Viral Proteins / genetics
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Viral Proteins / metabolism
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Virus Activation / drug effects
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Virus Latency / drug effects
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Virus Latency / genetics*
Substances
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BHRF1 protein, Human herpesvirus 4
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BZLF1 protein, Herpesvirus 4, Human
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Trans-Activators
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Viral Proteins
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Mixed Function Oxygenases
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TET1 protein, human
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Tetradecanoylphorbol Acetate