Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient MEFs). Mus musculus

Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Overall design: Examination of gene expression in response to PolyI:C in WT and G9a deficient MEFs

有效的抗病毒免疫，有赖于受感染细胞或经病毒来源核酸激活的细胞合成I型干扰素（type I interferon, IFN），后者可激活众多抗病毒基因的转录。然而，过度强烈或持续存在的干扰素表达，是引发炎症性与自身免疫性疾病的常见诱因。本研究阐明了一种表观遗传调控机制，该机制可决定细胞在应答外源信号时，干扰素与干扰素刺激基因表达的细胞类型特异性差异。我们发现，组蛋白H3第9位赖氨酸的二甲基化修饰（H3K9me2）可抑制干扰素以及干扰素诱导的抗病毒基因的表达。我们证实，在干扰素及干扰素刺激基因（IFN stimulated genes, ISG）区域的H3K9me2水平，与成纤维细胞和树突状细胞中干扰素及ISG表达的范围和幅度呈负相关。因此，对介导H3K9me2生成的关键酶——赖氨酸甲基转移酶G9a进行基因敲除或药理学失活，可使成纤维细胞表型转化为高效合成干扰素的细胞，并赋予这些细胞抵抗致病性RNA病毒的能力。综上，本研究表明H3K9me2及其丰度调控酶，是天然抗病毒免疫的关键调控因子。整体实验设计：检测野生型（wild type, WT）与G9a缺陷型小鼠胚胎成纤维细胞（MEFs）在应答聚肌胞苷酸（PolyI:C）时的基因表达情况。