SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells. Hye Kyung Lee et al. identify additional candidate enhancers linked to the ACE2 promoters producing biologically active ACE2, the receptor for SARS-CoV-2. They also demonstrate JAK inhibitors suppress the interferon-induced genetic programs, including ACE2 expression, in human airway epithelial cells.
【저자키워드】 High-throughput screening, Gene regulation, 【초록키워드】 Transcriptome, SARS-CoV-2, ACE2, Baricitinib, Gene Expression, SARS-COV-2 infection, Genetic, interferons, interferon, angiotensin-converting enzyme 2, inhibitors, airway, RNA-Seq, cells, hyperinflammation, epithelial cells, ruxolitinib, jak inhibitors, cell tropism, receptor, ACE2 expression, Jak, expression, JAK inhibitor, COVID-19 patients, Angiotensin-converting enzyme, Janus kinase, angiotensin, human airway epithelial cells, ACE2 gene, the cell, transcriptomes, Human airway epithelium, Regulation, enhancers, locus, human airway, ChIP-seq, element, promoter, enhancer, bronchial cells, Intronic, Cell, highlight, identify, activated, activate, suppress, producing, human airway epithelial, activating, 【제목키워드】 ACE2, Transcription, JAK inhibitor, Activation, isoform, Cell, human airway epithelial,