Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways

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 coro-naviruses 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 infec-tion. Here, we perform bioinformatic analyses to hypothesize on ACE2 gene regulation in two different physiological contexts, identifying putative regulato-ry elements of ACE2 expression. We perform functional validation of our compu-tational predictions via targeted CRISPR-Cas9 deletions of these elements in vitro, finding them responsive to immune signaling and oxidative-stress path-ways. 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.

Automated summary

This study makes use of bioinformatic analysis to propose hypotheses for ACE2 gene regulation and validates these hypotheses through functional experiments. It identifies regulatory elements associated with immune signaling and oxidative stress pathways. The findings contribute to our understanding of ACE2 gene regulation under normal conditions and immune challenges, supporting further research on these regulatory mechanisms in the context of current and future SARS-related virus infection/disease.