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Principal Investigator: Jian Xu
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2021
Award: $441,479
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
There is a pressing urgency to understand the regulatory mechanisms that control the expression of ACE2, the
cellular receptor for the new coronavirus SARS-CoV-2, in human cells under physiological and pathological
conditions. The binding between ACE2 and the SARS-CoV-2 spike protein, along with proteolytic cleavage of
ACE2, facilitates entry of the coronavirus into target cells, viral replication, and transmission. As such, ACE2
has been proposed as a key factor in virus infectivity and disease pathology. Although ACE2 is hijacked by
SARS-CoV-2 in the pathogenesis of COVID-19, its primary physiological role is to counteract tissue injury and
inflammation as part of the renin-angiotensin system (RAS). The expression of ACE2 is restricted to specific
tissue-resident cell types, developmentally regulated, and highly responsive to physiological (e.g. sex
hormones) and pathological (e.g. inflammation or virus infection) signals. By surveying the epigenetic
landscapes at the human ACE2 locus in the major ACE2-expressing cell types, we identified a set of gene-
distal cis-regulatory elements (CREs) displaying tissue-specific activity, consistent with putative cell type-
specific enhancer elements for ACE2. The molecular basis for the tissue- and developmental stage-specific
expression of ACE2 is unknown, and the regulatory mechanisms controlling ACE2 expression in response to
physiological and pathological signals remain unexplored, highlighting a critical gap in knowledge. Without an
in-depth understanding of the molecular and cellular pathways that control ACE2 expression, the genetic or
pharmacological modulation of ACE2 as an approach to therapy for COVID-19 will likely remain unreachable.
The objective of this project is to close a critical gap in our understanding of the transcriptional mechanisms
controlling ACE2 expression under normal and pathological conditions. The central hypothesis is that ACE2
expression is controlled by combinations of tissue-specific CREs to recruit cell type-specific and/or signal-
dependent transcription factors. This hypothesis has been formulated on the basis of the tissue-specific
expression profiles of ACE2 in human cells, the presence of multiple gene-distal CREs demarcated by active
chromatin signatures in ACE2-expressing cells, and the differential effects on ACE2 expression upon
physiological or pathological stimulations. Guided by these findings, this hypothesis will be tested by two
specific aims: 1) Determine the functional roles of tissue-specific cis-regulatory elements in controlling ACE2
expression and its responses to stimuli; 2) Identify and characterize chromatin regulatory complexes
responsible for ACE2 expression by CRISPR/dCas9-mediated affinity purification. Together, by focusing on the
validated entry receptor for SARS-CoV-2, our studies will not only advance our mechanistic understanding of
critical aspects of viral susceptibility and post-infection pathology, but also establish a much-needed resource
of candidate cis- and trans-regulatory factors required for ACE2 expression in human cells, thus facilitating
ongoing development of innovative strategies to leverage ACE2 as targeted therapies against COVID-19.
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