Ace2 and Tmprss2 Expressions Are Regulated by Dhx32 and Influence the Gastrointestinal Symptoms Caused by SARS-CoV-2

Abstract

Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for Tmprss2 and Ace2 mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both Tmprss2 and Ace2 are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both Tmprss2 and Ace2. Dhx32 was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both Tmprss2 and Ace2 were located at the same module that is significantly associated with other GI-related traits. Protein–protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19.

ACE and ACE2 catalytic activity in the fecal content along the gut

“…ACE2 was evenly distributed and active from the terminal ileum to the DC. These data are in accordance with data from other studies reporting that ACE2 is expressed throughout the small and large intestine, 9,[33][34][35][36][37] although some studies have reported that ACE2 expression is higher in the ileum than in the colon. [34][35][36][37] Intestinal ACE2 actively removes C-terminal single neutral amino acid from nutrient peptides, which are then uptaken by the neutral amino acid transporter B 0 AT1.…”

“…These data are in accordance with data from other studies reporting that ACE2 is expressed throughout the small and large intestine, 9,[33][34][35][36][37] although some studies have reported that ACE2 expression is higher in the ileum than in the colon. [34][35][36][37] Intestinal ACE2 actively removes C-terminal single neutral amino acid from nutrient peptides, which are then uptaken by the neutral amino acid transporter B 0 AT1. 38,39 Interestingly, it has been reported that ACE2 expression is required for the expression, proper trafficking, and functioning of B 0 AT1, 39 which is abundantly expressed in the ileum.…”

ABO Blood System and COVID-19 Susceptibility: Anti-A and Anti-B Antibodies Are the Key Points

“…Moreover, the implications of ACE2 upregulation would lead to specific studies based on different symptoms in old and young patients. Patients with ACE2 overexpression in the gastrointestinal tract are associated with more diarrhea ( 59 ). In fact, there is evidence demonstrating a direct association between endothelitis and severe COVID-19 ( 60 ).…”

HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression

“…To identify the regulators of SHMT1 in RCC, we performed an analysis by genome‐wide association studies (GWAS). As a high‐energy resource of GWAS, the BXD family is widely used in the study of medicine and disease mechanism, including the search for the regulatory network of genes in diseases 30,31 . Figure 4A shows the gene expression levels of Shmt1 in kidney tissue from 53 BXD mouse strains and their corresponding parental strains.…”