Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways
Summary: The angiotensin-converting enzyme 2 (ACE2) protein is a key catalytic regulator of the renin-angiotensin system (RAS), involved in fluid homeostasis and blood pressure modulation. ACE2 also serves as a cell-surface receptor for some coronaviruses such as SARS-CoV and SARS-CoV-2. Improved ch...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222008860 |
| _version_ | 1811238169835732992 |
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| author | Daniel Richard Pushpanathan Muthuirulan Jennifer Aguiar Andrew C. Doxey Arinjay Banerjee Karen Mossman Jeremy Hirota Terence D. Capellini |
| author_facet | Daniel Richard Pushpanathan Muthuirulan Jennifer Aguiar Andrew C. Doxey Arinjay Banerjee Karen Mossman Jeremy Hirota Terence D. Capellini |
| author_sort | Daniel Richard |
| collection | DOAJ |
| description | Summary: The angiotensin-converting enzyme 2 (ACE2) protein is a key catalytic regulator of the renin-angiotensin system (RAS), involved in fluid homeostasis and blood pressure modulation. ACE2 also serves as a cell-surface receptor for some coronaviruses such as SARS-CoV and SARS-CoV-2. Improved characterization of ACE2 regulation may help us understand the effects of pre-existing conditions on COVID-19 incidence, as well as pathogenic dysregulation following viral infection. Here, we perform bioinformatic analyses to hypothesize on ACE2 gene regulation in two different physiological contexts, identifying putative regulatory elements of ACE2 expression. We perform functional validation of our computational predictions via targeted CRISPR-Cas9 deletions of these elements in vitro, finding them responsive to immune signaling and oxidative-stress pathways. This contributes to our understanding of ACE2 gene regulation at baseline and immune challenge. Our work supports pursuit of these putative mechanisms in our understanding of infection/disease caused by current, and future, SARS-related viruses such as SARS-CoV-2. |
| first_indexed | 2024-04-12T12:37:06Z |
| format | Article |
| id | doaj.art-44c0b628ea214c9c84b80ab8741b75bf |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T12:37:06Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-44c0b628ea214c9c84b80ab8741b75bf2022-12-22T03:32:52ZengElsevieriScience2589-00422022-07-01257104614Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathwaysDaniel Richard0Pushpanathan Muthuirulan1Jennifer Aguiar2Andrew C. Doxey3Arinjay Banerjee4Karen Mossman5Jeremy Hirota6Terence D. Capellini7Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USADepartment of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USADepartment of Biology, University of Waterloo, Waterloo, ON N2L3G1, CanadaDepartment of Biology, University of Waterloo, Waterloo, ON N2L3G1, CanadaDepartment of Biology, University of Waterloo, Waterloo, ON N2L3G1, Canada; Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK S7N5B4, CanadaDepartment of Medicine, McMaster University, Hamilton, ON L8N 3Z5, CanadaDepartment of Biology, University of Waterloo, Waterloo, ON N2L3G1, Canada; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, CanadaDepartment of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, 02142 MA, USA; Corresponding authorSummary: The angiotensin-converting enzyme 2 (ACE2) protein is a key catalytic regulator of the renin-angiotensin system (RAS), involved in fluid homeostasis and blood pressure modulation. ACE2 also serves as a cell-surface receptor for some coronaviruses such as SARS-CoV and SARS-CoV-2. Improved characterization of ACE2 regulation may help us understand the effects of pre-existing conditions on COVID-19 incidence, as well as pathogenic dysregulation following viral infection. Here, we perform bioinformatic analyses to hypothesize on ACE2 gene regulation in two different physiological contexts, identifying putative regulatory elements of ACE2 expression. We perform functional validation of our computational predictions via targeted CRISPR-Cas9 deletions of these elements in vitro, finding them responsive to immune signaling and oxidative-stress pathways. This contributes to our understanding of ACE2 gene regulation at baseline and immune challenge. Our work supports pursuit of these putative mechanisms in our understanding of infection/disease caused by current, and future, SARS-related viruses such as SARS-CoV-2.http://www.sciencedirect.com/science/article/pii/S2589004222008860Biological sciencesMolecular biologyImmunologyVirology |
| spellingShingle | Daniel Richard Pushpanathan Muthuirulan Jennifer Aguiar Andrew C. Doxey Arinjay Banerjee Karen Mossman Jeremy Hirota Terence D. Capellini Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways iScience Biological sciences Molecular biology Immunology Virology |
| title | Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways |
| title_full | Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways |
| title_fullStr | Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways |
| title_full_unstemmed | Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways |
| title_short | Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways |
| title_sort | intronic regulation of sars cov 2 receptor ace2 expression mediated by immune signaling and oxidative stress pathways |
| topic | Biological sciences Molecular biology Immunology Virology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222008860 |
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