Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways
Daniel Richard,
Pushpanathan Muthuirulan,
Jennifer Aguiar,
Andrew C. Doxey,
Arinjay Banerjee,
Karen Mossman,
Jeremy Hirota,
Terence D. Capellini
Affiliations
Daniel Richard
Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
Pushpanathan Muthuirulan
Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
Jennifer Aguiar
Department of Biology, University of Waterloo, Waterloo, ON N2L3G1, Canada
Andrew C. Doxey
Department of Biology, University of Waterloo, Waterloo, ON N2L3G1, Canada
Arinjay Banerjee
Department 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, Canada
Karen Mossman
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada
Jeremy Hirota
Department 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, Canada
Terence D. Capellini
Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, 02142 MA, USA; Corresponding author
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.