Regulation of the ACE2 locus in human airways cells.
Regulation of the ACE2 locus in human airways cells.
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人类气道细胞中 ACE2 基因座的调节。
DOI：
10.1101/2020.10.04.325415
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hennighausen,Lothar
中科院分区：
文献类型：
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作者：
Lee,HyeKyung;Jung,Olive;Hennighausen,Lothar
血管紧张素转换酶2 （ACE2）受体是SARS-CoV-2进入气道上皮的门户1,2，病毒感染后强烈的炎症反应是COVID-19患者的标志。破译ACE2基因的调控对于理解SARS-CoV-2感染的细胞趋向性至关重要。在这里，我们确定了人类原代气道细胞和肺组织中ACE2基因座的候选调控元件。激活组蛋白和启动子标记以及Pol II负载表征了内含子dACE2，并定义了距离真正的ACE2启动子远端的新候选增强子和额外的内含子。在干扰素处理的原代支气管细胞中，dACE2和较低程度的ACE2 RNA水平升高，而用于治疗COVID-19患者的Janus激酶（JAK）抑制剂减轻了这种诱导。我们的分析提供了控制ACE2位点的调控元件的见解，并强调JAK抑制剂是抑制支气管细胞中干扰素激活的遗传程序的合适工具。
The angiotensin-converting enzyme 2 (ACE2) receptor is the gateway for SARS-CoV-2 to airway epithelium1,2 and the strong inflammatory response after viral infection is a hallmark in COVID-19 patients. Deciphering the regulation of the ACE2 gene is paramount for understanding the cell tropism of SARS-CoV-2 infection. Here we identify candidate regulatory elements in the ACE2 locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronic dACE2 and define novel candidate enhancers distal to the genuine ACE2 promoter and within additional introns. dACE2, and to a lesser extent ACE2, RNA levels increased in primary bronchial cells treated with interferons and this induction was mitigated by Janus kinase (JAK) inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into regulatory elements governing the ACE2 locus and highlight that JAK inhibitors are suitable tools to suppress interferon-activated genetic programs in bronchial cells.