Department of Dermatology, Southwest Hospital, Third Military Medical University(Army Medical University), Chongqing, 400038, China.
Laboratory of Human Health and Genome Regulation, ABLife Inc., Wuhan, Hubei 430075, China; Center for Genome Analysis, ABLife Inc., Wuhan, Hubei 430075, China.
Mol Immunol. 2021 Apr;132:132-141. doi: 10.1016/j.molimm.2021.01.030. Epub 2021 Feb 13.
PKR, also known as EIF2AK2, is an IFN-stimulated gene (ISG) and shows a higher expression in probands with systemic lupus erythematosus (SLE), which is likely responsible for the impaired translational and proliferative responses to mitogens in T cells from SLE patients. In this study, we overexpressed EIF2AK2 in HeLa cells to study EIF2AK2-regulated genes using RNA-seq technology, followed by bioinformatic analysis of target genes of EIF2AK2-regulated transcriptional factors (TFs). Overexpression of EIF2AK2 promotes HeLa cell apoptosis. EIF2AK2 selectively represses the transcription of histone protein genes associated with SLE, immune response genes and TF genes, which was validated by RT-qPCR experiments. Analysis of motifs overrepresented in the promoter regions of EIF2AK2-regulated genes revealed eighteen EIF2AK2-regulated TFs involved in establishing the EIF2AK2 network. Eight out of these predicted EIF2AK2-regulated TFs were further verified by RT-qPCR selectively in both HeLa and Jurkat cells, and most such as HEY2, TFEC, BATF2, GATA3 and ATF3 and FOXO6 are known to regulate immune response. Our results suggest that the dsRNA-dependent kinase EIF2AK2 selectively regulates the transcription of immune response and SLE-associated histone protein genes, and such a selectivity is likely to be operated by EIF2AK2-targeted TFs. The EIF2AK2-TFs axis potentially offers new therapeutic targets for counteracting immunological disease in the future.
PKR，也称为 EIF2AK2，是一种 IFN 刺激基因（ISG），在红斑狼疮（SLE）患者中表现出更高的表达水平，这可能导致 SLE 患者 T 细胞对有丝分裂原的翻译和增殖反应受损。在这项研究中，我们通过 RNA-seq 技术在 HeLa 细胞中过表达 EIF2AK2，以研究 EIF2AK2 调节的基因，然后对 EIF2AK2 调节的转录因子（TF）的靶基因进行生物信息学分析。EIF2AK2 的过表达促进了 HeLa 细胞的凋亡。EIF2AK2 选择性地抑制与 SLE、免疫反应基因和 TF 基因相关的组蛋白蛋白基因的转录，这通过 RT-qPCR 实验得到了验证。对 EIF2AK2 调节基因启动子区域中过表达的基序进行分析，揭示了 18 个参与建立 EIF2AK2 网络的 EIF2AK2 调节 TF。其中 8 个预测的 EIF2AK2 调节 TF 通过 RT-qPCR 选择性地在 HeLa 和 Jurkat 细胞中进一步验证，其中大多数如 HEY2、TFEC、BATF2、GATA3 和 ATF3 和 FOXO6 已知可调节免疫反应。我们的结果表明，dsRNA 依赖性激酶 EIF2AK2 选择性地调节免疫反应和与 SLE 相关的组蛋白蛋白基因的转录，这种选择性可能由 EIF2AK2 靶向的 TF 操作。EIF2AK2-TFs 轴可能为未来对抗免疫性疾病提供新的治疗靶点。
