JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells.
Hye Kyung LeeOlive JungLothar HennighausenPublished in: Communications biology (2021)
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.
Keyphrases
- rna seq
- single cell
- angiotensin converting enzyme
- sars cov
- angiotensin ii
- high throughput
- gene expression
- induced apoptosis
- dna methylation
- genome wide
- respiratory syndrome coronavirus
- endothelial cells
- transcription factor
- signaling pathway
- cell cycle arrest
- induced pluripotent stem cells
- dendritic cells
- poor prognosis
- circulating tumor cells
- multiple sclerosis
- binding protein
- stem cells
- pluripotent stem cells
- oxidative stress
- endoplasmic reticulum stress
- mesenchymal stem cells
- cell therapy
- tyrosine kinase
- long non coding rna