Transcriptional regulation of human cyclic GMP-AMP synthase gene
Transcriptional regulation of human cyclic GMP-AMP synthase gene
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DOI：
10.1016/j.cellsig.2019.109355
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发表时间：
2019-10-01
影响因子：
4.8
通讯作者：
Xu, Hua-Guo
中科院分区：
文献类型：
--
作者：
Chen, Hai-Yan;Pang, Xiao-Yu;Xu, Hua-Guo
环GMP-AMP合酶（cGAS，cGAMP synthase）在自身免疫性疾病、抗肿瘤反应、抗衰老和抗炎反应中发挥重要作用。许多研究集中在cGAS介导的信号通路。然而，cGAS基因的转录机制在很大程度上仍然未知。在这里，我们克隆了cGAS启动子区域，并表征了控制cGAS转录活性的分子机制。通过一系列的5'端缺失和启动子构建，我们证明了该区域（相对于转录起始位点的-414至+76）足够启动子活性。该启动子区域中Sp1和CREB结合位点的突变导致cGAS启动子活性明显降低。Sp1和CREB的过表达可明显增强cGAS启动子活性，而内源性Sp1和CREB的敲低可明显抑制cGAS启动子活性。通过染色质免疫沉淀测定验证Sp1和CREB与cGAS启动子区域的体内结合。这些结果表明转录因子Spl和CREB调节cGAS基因的转录。
Cyclic GMP-AMP synthase (cGAS, cGAMP synthase) plays crucial roles in autoimmune disease, anti-tumor response, anti-senescence and anti-inflammatory response. Many studies have focused on cGAS-mediated signaling pathway. However, transcriptional mechanisms of cGAS gene have remained largely unknown. Here, we cloned the cGAS promoter region and characterized the molecular mechanisms controlling the cGAS transcriptional activity. By a series of 5' deletion and promoter constructions, we showed that the region (-414 to +76 relatives to the transcription start site) was sufficient for promoter activity. Mutation of Sp1 and CREB binding sites in this promoter region led to an apparent reduction of the cGAS promoter activity. Overexpression of Sp1 and CREB could obviously enhance promoter activity, whereas knocking-down of endogenous Sp1 and CREB markedly restrained the cGAS promoter activity. Sp1 and CREB binding to the cGAS promoter region in vivo was verified by Chromatin immunoprecipitation assay. These results pointed out that transcription factors Spl and CREB regulate the transcription of the cGAS gene.