Abstract
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
Highlights
Epigenetic modulation of the structure of chromatin, including DNA modifications and posttranslational modifications of histones, is critical for the regulation of gene expression [1, 2]
We show a unique mechanism through which bromodomain protein 4 (BRD4) inhibition broadly inhibits attachment of DNA and RNA viruses through DNA damage-dependent antiviral innate immune activation via the Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway, in both cell culture and an animal model
STING-associated innate immune signaling has been considered to be a new possibility for cancer therapy, and STING agonists have been tested in early clinical trials
Summary
Epigenetic modulation of the structure of chromatin, including DNA modifications and posttranslational modifications of histones, is critical for the regulation of gene expression [1, 2]. Many enzymes involved in epigenetic modulation of chromatin have been identified. These include DNA methyltransferases and DNA demethylases; histone acetyltransferases and histone deacetylases; and lysine methyltransferases and lysine demethylases. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factors [3]. Acetyl groups can serve as a platform for recruitment of histone acetylation readers to participate in gene transcription, DNA replication, DNA repair or chromatin condensation [5]. Dysregulation of epigenetic modifications is associated with various human diseases, such as cancer and neurodevelopmental disorders [8, 9]
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