Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2

Nersisyan, Stepan; Shkurnikov, M. Yu.; Turchinovich, Andrey; Knyazev, E N; Tonevitsky, Alexander G.

doi:10.1371/journal.pone.0235987

Cited by 84 publications

(105 citation statements)

References 53 publications

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“… Russia To explore the landscape of ACE2 and TMPRSS2 regulation mediated by miRNAs and isomiRs in different human organs using bioinformatic analysis of publicly available paired miRNA/mRNA- sequencing datasets. ( Nersisyan et al, 2020b ) 29 Paniri A June 1, 2020. Iran To perform a comprehensive computational analysis of TMPRSS2 to investigate pathways, expression profiles, epigenetic mechanisms, SNPs of this gene influencing miRNA function.…”

Section: Resultsmentioning

confidence: 99%

The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review

Marchi¹,

Sugita²,

Centa³

et al. 2021

Infection, Genetics and Evolution

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MicroRNAs are gene expression regulators, associated with several human pathologies, including the ones caused by virus infections. Although their role in infection diseases is not completely known, they can exert double functions in the infected cell, by mediating the virus infection and/or regulating the immunity-related gene targets through complex networks of virus-host cell interactions. In this systematic review, the Pubmed, EMBASE, Scopus, Lilacs, Scielo, and EBSCO databases were searched for research articles published until October 22nd, 2020 that focused on describing the role, function, and/or association of miRNAs in SARS-CoV-2 human infection and COVID-19. Following the PRISMA 2009 protocol, 29 original research articles were selected. Most of the studies reported miRNA data based on the genome sequencing of SARS-CoV-2 isolates and computational prediction analysis. The latter predicted, by at least one independent study, 1266 host miRNAs to target the viral genome. Thirteen miRNAs were identified by four independent studies to target SARS-CoV-2 specific genes, suggested to act by interfering with their cleavage and/or translation process. The studies selected also reported on viral and host miRNAs that targeted host genes, on the expression levels of miRNAs in biological specimens of COVID-19 patients, and on the impact of viral genome mutations on miRNA function. Also, miRNAs that regulate the expression levels of the ACE2 and TMPRSS2 proteins, which are critical for the virus entrance in the host cells, were reported. In conclusion, despite the limited number of studies identified, based on the search terms and eligibility criteria applied, this systematic review provides evidence on the impact of miRNAs on SARS-CoV-2 infection and COVID-19. Although most of the reported viral/host miRNAs interactions were based on in silico prediction analysis, they demonstrate the relevance of the viral/host miRNA interaction for viral activity and host responses. In addition, the identified studies highlight the potential use of miRNAs as therapeutic targets against COVID-19, and other viral human diseases (This review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) database (#CRD42020199290).

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Section: Resultsmentioning

confidence: 99%

The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review

Marchi¹,

Sugita²,

Centa³

et al. 2021

Infection, Genetics and Evolution

View full text Add to dashboard Cite

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“…Together, these analyses clearly demonstrate that the androgen deprivation has an effect on the expression of TMPRSS2 and ACE2, particularly in the lung, small intestine, and kidney. Though there was a discrepancy concerning transcript and protein levels of TMPRSS2 in the tested tissues - particularly in the kidney, post-transcriptional regulation of TMPRSS2 by androgen regulated microRNA could not be ruled out (Nersisyan et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Deng

Rasool

Russell

et al. 2020

Preprint

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The COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm and associated oncogenic signaling. Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and co-receptor TMPRSS2 by androgen in mouse tissues and human prostate and lung cell lines. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. In an overexpression model, and the prostate and lung cells, Camostat – a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike protein, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens such as enzalutamide/AR-PROTAC, or Camostat treatment attenuated the SARS-CoV-2 S-mediated entry in lung and prostate cells. Together, our preclinical data provide a strong rationale for clinical evaluations of the TMPRSS2 inhibitors, androgen-deprivation therapy and androgen receptor antagonists alone or in combination with anti-viral drugs as early as clinically possible to prevent inflammation driven COVID-19 progression.

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“…In terms of the MERS-CoV genome, miR-92 was predicted to target the 3′-UTR, while miR-130 and miR-199 were predicted to target the 5′-UTR. While host miRNA-mediated regulation of MERS-CoV is not well explored, it is interesting to note that miR-199a has been previously identified to regulate TMPRSS2 expression in the liver, stomach, and uterine corpus, as this protease is critical for SARS-CoV-2, SARS-CoV, and MERS-CoV entry into cells [ 78 ]. Therefore, upon further analysis and experimental validation to determine whether these are true miRNA binding sites, the roles of these miRNAs in modulating MERS-CoV infection, along with other related viruses, can be explored.…”

Section: Potential Roles and Binding Sites Of Micrornas In The Sars-cmentioning

confidence: 99%

MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19

Hum

Loiselle

Ahmed

et al. 2021

Drugs

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Coronaviruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic, present a significant threat to human health by inflicting a wide variety of health complications and even death. While conventional therapeutics often involve administering small molecules to fight viral infections, small non-coding RNA sequences, known as microRNAs (miRNAs/miR-), may present a novel antiviral strategy. We can take advantage of their ability to modulate host–virus interactions through mediating RNA degradation or translational inhibition. Investigations into miRNA and SARS-CoV-2 interactions can reveal novel therapeutic approaches against this virus. The viral genomes of SARS-CoV-2, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) were searched using the Nucleotide Basic Local Alignment Search Tool (BLASTn) for highly similar sequences, to identify potential binding sites for miRNAs hypothesized to play a role in SARS-CoV-2 infection. miRNAs that target angiotensin-converting enzyme 2 (ACE2), the receptor used by SARS-CoV-2 and SARS-CoV for host cell entry, were also predicted. Several relevant miRNAs were identified, and their potential roles in regulating SARS-CoV-2 infections were further assessed. Current treatment options for SARS-CoV-2 are limited and have not generated sufficient evidence on safety and efficacy for treating COVID-19. Therefore, by investigating the interactions between miRNAs and SARS-CoV-2, miRNA-based antiviral therapies, including miRNA mimics and inhibitors, may be developed as an alternative strategy to fight COVID-19.

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Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2

Cited by 84 publications

References 53 publications

The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review

The role of microRNAs in modulating SARS-CoV-2 infection in human cells: a systematic review

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

MicroRNA Mimics or Inhibitors as Antiviral Therapeutic Approaches Against COVID-19

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