Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens [RNA-Seq]

Epigenetic regulation is based upon a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets to treat a range of diseases including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach to control infection, persistence, and the resulting recurrent disease. The histone methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3 enriched chromatin domains. However, while EZH2/1 are implicated in repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and anti-pathogen pathways as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses. Overall design: The dataset includes gene expression profiling of human foreskin fibroblast (HFF) cells and mouse trigeminal ganglia. HFF cells were treated with GSK126 (30 µM) or vehicle for 1 hour, 2 hours, and 5 hours with biological triplicates. Trigeminal ganglia from mock or HSV-1 latently infected BALB/c mice were explanted in media containing GSK126 (30 µM) or vehicle for 12 hours with biological triplicates (pooled 4-5 trigeminal ganglia per replicate).

表观遗传调控（Epigenetic regulation）依赖于由多种复合物构成的调控网络，这类复合物可修饰染色质特征与基因组结构，进而影响基因表达、细胞命运及个体发育。因此，表观遗传调控因子可作为新型治疗靶点，用于治疗包括恶性肿瘤在内的多种疾病。
感染性病原体（如疱疹病毒）同样受细胞表观遗传机器的调控，而表观遗传疗法亦为控制感染、持续感染及由此引发的复发性疾病提供了全新策略。
组蛋白甲基转移酶（histone methyltransferases）EZH2与EZH1（合称EZH2/1）属于表观遗传阻遏因子，可通过传播富集抑制性H3K27me3修饰的染色质结构域来抑制基因转录。然而，尽管EZH2/1被证实可抑制疱疹病毒的基因表达，该类酶的抑制剂却可在体外与体内抑制单纯疱疹病毒（HSV）的初次感染。
此外，在潜伏感染的感觉神经节中诱导HSV复激活后，这类化合物可阻断裂解性病毒复制。这种抑制效应与多种炎症、应激及抗病原体通路的激活，以及免疫细胞向体内感染部位的招募增强密切相关。尤为重要的是，EZH2/1抑制剂可诱导细胞产生抗病毒状态，该状态同样可抑制DNA病毒（人巨细胞病毒hCMV、腺病毒Adenovirus）与RNA病毒（寨卡病毒Zika virus）的感染。
综上，EZH2/1抑制剂通过激活细胞抗病毒与免疫应答，具备作为广谱抗病毒药物的巨大潜力。
整体实验设计：本数据集包含人包皮成纤维细胞（HFF）与小鼠三叉神经节（trigeminal ganglia）的基因表达谱分析。将HFF细胞用GSK126（30 μM）或溶剂对照处理1小时、2小时及5小时，每组设置生物学重复三次。从模拟感染或HSV-1潜伏感染的BALB/c小鼠中分离三叉神经节，将其在含GSK126（30 μM）或溶剂对照的培养基中外植培养12小时，每组设置生物学重复三次（每个重复样本混合4-5个三叉神经节）。