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.

由表观遗传修饰调控的染色质动力学对基因组稳定性和基因表达至关重要。在人类疾病的发病机理中已经发现了多种表观遗传机制。在这里，我们通过使用GFP报告基因检测方法检查了十种表观遗传因子对伪狂犬病病毒（PRV）感染的影响。在癌症中比病毒感染受到更多关注的溴结构域蛋白4（BRD4）抑制剂被发现对PRV以及各种DNA和RNA病毒具有实质性的抗病毒活性。我们进一步证明了对BRD4的抑制可增强强大的先天免疫应答。BRD4抑制还会破坏染色质结构并诱导DNA损伤反应，从而触发cGAS介导的先天免疫的激活并增加宿主对病毒感染的抵抗力体外和体内。从机理上讲，BRD4抑制对病毒感染的抑制作用主要归因于病毒附着的减弱。我们的发现揭示了BRD4抑制通过其抑制病毒感染并指出其对病毒感染性疾病的有效治疗价值的独特机制。