Identification of Transcription Factors Regulating SARS-CoV-2 Entry Genes in the Intestine

Chen, Lei; Marishta, A.; Verzi, Michael P.

doi:10.1016/j.jcmgh.2020.08.005

Cited by 21 publications

(25 citation statements)

References 10 publications

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“…Additional studies are warranted to further delineate mechanisms through which the microbiome regulates Ace2 expression in the respiratory and gastrointestinal tracts. A recent study identified transcriptional factors regulating Ace2 expression in the gut [ 18 ], including Gata4, which is known to be regulated by the microbiota [ 19 ]. The partial recapitulation of the GF phenotype that we observed with antibiotics further raises the prospect of differential temporal dynamics of the relationships between the microbiome and the lung versus gut with respect to Ace2 expression.…”

Section: Discussionmentioning

confidence: 99%

Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome

Koester

Lachance

et al. 2021

PLoS ONE

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COVID-19 (coronavirus disease 2019) patients exhibiting gastrointestinal symptoms are reported to have worse prognosis. Ace2 (angiotensin-converting enzyme 2), the gene encoding the host protein to which SARS-CoV-2 spike proteins bind, is expressed in the gut and therefore may be a target for preventing or reducing severity of COVID-19. Here we test the hypothesis that Ace2 expression in the gastrointestinal and respiratory tracts is modulated by the microbiome. We used quantitative PCR to profile Ace2 expression in germ-free mice, conventional raised specific pathogen-free mice, and gnotobiotic mice colonized with different microbiota. Intestinal Ace2 expression levels were significantly higher in germ-free mice compared to conventional mice. A similar trend was observed in the respiratory tract. Intriguingly, microbiota depletion via antibiotics partially recapitulated the germ-free phenotype, suggesting potential for microbiome-mediated regulation of Ace2 expression. Variability in intestinal Ace2 expression was observed in gnotobiotic mice colonized with different microbiota, partially attributable to differences in microbiome-encoded proteases and peptidases. Together, these data suggest that the microbiome may be one modifiable factor determining COVID-19 infection risk and disease severity.

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Section: Discussionmentioning

confidence: 99%

Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome

Koester

Lachance

et al. 2021

PLoS ONE

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“…Mechanisms driving expression of ACE2 and its co-receptor TMPRSS2 remain unclear. Using an elegant epigenetic approach coupled with genetically manipulated murine models, Chen et al, found CDX2, HNF4, SMAD4 and GATA transcription factors bind near Ace2 and Tmprss2 resulting in altered chromatin looping and epigenetic modi cations with signi cant impact on ACE2 and TMPRSS2 gene expression 19 .…”

Section: Discussionmentioning

confidence: 99%

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s Disease

Toyonaga

Araba

Kennedy

et al. 2021

Preprint

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Background and Aims: The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. Methods: We examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Results: Colonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037). Conclusion: Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

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“…Transcriptional regulatory network of hyperin ammation in cerebral cortex. We then analyzed the signaling network regulated by transcription factors (TFs), which might associate with the susceptibility or severity of SARS-CoV-2 infection 24 . Among 745 TFs identi ed in rhesus macaque based on human transcriptional regulatory interactions of TRRUST database 25 , 567 showed dysregulation in the infected tissues, especially in cerebral cortex, cerebellum and right ventricle (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques

Yang

Gao

et al. 2021

Preprint

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SARS-CoV-2 infection causes complicated clinic manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various tissues/organs examined, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Neuronal receptor NRP1 expression showed a significant induction by SARS-CoV-2 in cerebral cortex, which might be responsible for a higher infectivity and consequent inflammatory response. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

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Identification of Transcription Factors Regulating SARS-CoV-2 Entry Genes in the Intestine

Cited by 21 publications

References 10 publications

Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome

Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome

Increased Colonic Expression of ACE2 Associates with Poor Prognosis in Crohn’s Disease

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques

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