JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (RNA-seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA679047 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2021-04-23 | GSE161665 | GEO
Project description:JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells
| PRJNA679038 | ENA
Project description: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 dACE 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.
2021-04-23 | GSE161664 | GEO
Project description: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 dACE 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.
2021-04-23 | GSE161663 | GEO
Project description:JAK inhibitors dampen activation of interferon-stimulated transcription of ACE2 isoforms in human airway epithelial cells (ChIP-seq)
| PRJNA679046 | ENA
Project description: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.
| S-EPMC8172581 | biostudies-literature
Project description:SARS-CoV-2 infections initiate cytokine storms and activate genetic programs leading to progressive hyperinflammation in multiple organs of patients with COVID-19. While it is known that COVID-19 impacts kidney function, leading to increased mortality, cytokine response of renal epithelium has not been studied in detail. Here, we report on the genetic programs activated in human primary proximal tubule (HPPT) cells by interferons and their suppression by ruxolitinib, a Janus kinase (JAK) inhibitor used in COVID-19 treatment. Integration of our data with those from patients with acute kidney injury and COVID-19, as well as other tissues, permitted the identification of kidney-specific interferon responses. Additionally, we investigated the regulation of the recently discovered isoform (dACE2) of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. Using ChIP-seq, we identified candidate interferon-activated enhancers controlling the ACE2 locus, including the intronic dACE2 promoter. Taken together, our study provides an in-depth understanding of genetic programs activated in kidney cells.
2021-02-03 | GSE161917 | GEO
Project description:Angiotensin-Converting Enzyme 2 (ACE2) binds SARS-CoV-2 spike protein and facilitates viral entry into the cell. ACE2 is expressed in the kidney and renal injury strongly impacts COVID-19 prognosis. In addition, a short, interferon-inducible isoform of ACE2, dACE2 was recently identified. Change in ACE2 expression has already been linked to several human nephropathies. However, these changes were not analyzed in context of dACE2 and regulation of ACE2 expression in the kidney remains unclear. Human primary Renal Proximal Tubule cells were used for all experiments. ChIP-seq analysis of histone modifications (H3K27ac, H3K4me3, K3K4me1), RNA polymerase loading and DNAse hypersensitive sites (DHS) were used to identify gene regulatory elements in the ACE2 locus. qRT-PCR was used to assess mRNA expression of ACE2, dACE2, TMPRSS2 and STAT1. RNA-seq was used to identify changes in global gene expression after cytokine treatment. Putative regulatory elements controlling dACE2 expression were identified using ChIP-seq profiles and RNA-seq mapping. qRT-PCR differentiating between ACE2 and dACE2 revealed that only dACE2 is interferon inducible. dACE2 mRNA was upregulated 300- and 600-fold by IFNα and IFNβ, respectively, while full length ACE2 was unchanged. Interferon stimulation also resulted in elevated STAT1 expression. JAK inhibitor ruxolitinib ablated both STAT1 and dACE2 expression after interferon treatment. RNA-seq analysis revealed approximately 1200 genes induced by IFNβ, largely innate immune response-related. We showed that human primary proximal tubules express ACE2 and its interferon-inducible short isoform, dACE2, from an intronic promoter. We also deliver new datasets identifying cytokine response genes in proximal tubule cells.
2021-02-03 | GSE161916 | GEO
Project description:Angiotensin-Converting Enzyme 2 (ACE2) binds SARS-CoV-2 spike protein and facilitates viral entry into the cell. ACE2 is expressed in the kidney and renal injury strongly impacts COVID-19 prognosis. In addition, a short, interferon-inducible isoform of ACE2, dACE2 was recently identified. Change in ACE2 expression has already been linked to several human nephropathies. However, these changes were not analyzed in context of dACE2 and regulation of ACE2 expression in the kidney remains unclear. Human primary Renal Proximal Tubule cells were used for all experiments. ChIP-seq analysis of histone modifications (H3K27ac, H3K4me3, K3K4me1), RNA polymerase loading and DNAse hypersensitive sites (DHS) were used to identify gene regulatory elements in the ACE2 locus. qRT-PCR was used to assess mRNA expression of ACE2, dACE2, TMPRSS2 and STAT1. RNA-seq was used to identify changes in global gene expression after cytokine treatment. Putative regulatory elements controlling dACE2 expression were identified using ChIP-seq profiles and RNA-seq mapping. qRT-PCR differentiating between ACE2 and dACE2 revealed that only dACE2 is interferon inducible. dACE2 mRNA was upregulated 300- and 600-fold by IFNα and IFNβ, respectively, while full length ACE2 was unchanged. Interferon stimulation also resulted in elevated STAT1 expression. JAK inhibitor ruxolitinib ablated both STAT1 and dACE2 expression after interferon treatment. RNA-seq analysis revealed approximately 1200 genes induced by IFNβ, largely innate immune response-related. We showed that human primary proximal tubules express ACE2 and its interferon-inducible short isoform, dACE2, from an intronic promoter. We also deliver new datasets identifying cytokine response genes in proximal tubule cells.
2021-02-03 | GSE161915 | GEO
Project description:SARS-CoV-2 infections initiate cytokine storms and activate genetic programs leading to progressive hyperinflammation in multiple organs of patients with COVID-19. While it is known that COVID-19 impacts kidney function, leading to increased mortality, cytokine response of renal epithelium has not been studied in detail. Here, we report on the genetic programs activated in human primary proximal tubule (HPPT) cells by interferons and their suppression by ruxolitinib, a Janus kinase (JAK) inhibitor used in COVID-19 treatment. Integration of our data with those from patients with acute kidney injury and COVID-19, as well as other tissues, permitted the identification of kidney-specific interferon responses. Additionally, we investigated the regulation of the recently discovered isoform (dACE2) of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. Using ChIP-seq, we identified candidate interferon-activated enhancers controlling the ACE2 locus, including the intronic dACE2 promoter. Taken together, our study provides an in-depth understanding of genetic programs activated in kidney cells.
| S-EPMC8321697 | biostudies-literature