Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting G9a Regulated m6A Modification Pathway to Hinder SARS-CoV-2 Replication

ABSTRACT: N6-methyladenosine (m6A) modification pathway is hijacked by several RNA viruses, including SARS-CoV-2, making it an attractive host-directed target for development of broad-spectrum antivirals. Here, we show that histone methyltransferase G9a, through its interaction with METTL3, regulates SARS-CoV-2 mediated rewiring of host m6A methylome to ultimately promote turnover, abundance, secretion and/or phosphorylation of various viral receptors and proteases, transcription factors, cytokines/chemokines, coagulation & angiogenesis associated proteins, and fibrosis markers. More importantly, drugs targeting G9a and its associated protein EZH2 are potent inhibitors of SARS-CoV-2 replication and reverse multi-omic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and COVID-19 patient PBMCs - with similar changes seen in multiorgan autopsy samples from COVID-19 patients. Altogether, we extend G9a function(s) beyond transcription to translational regulation during COVID-19 pathogenesis and show that targeting this master regulatory complex represents a new strategy (drug-class) that can be leveraged to combat emerging anti-viral resistance and infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282914 | GEO | 2025/04/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Targeting G9a Regulated m6A Modification Pathway to Hinder SARS-CoV-2 Replication

Project description:N6-methyladenosine (m6A) modification pathway is hijacked by several RNA viruses, including SARS-CoV-2, making it an attractive host-directed target for development of broad-spectrum antivirals. Here, we show that histone methyltransferase G9a, through its interaction with METTL3, regulates SARS-CoV-2 mediated rewiring of host m6A methylome to ultimately promote turnover, abundance, secretion and/or phosphorylation of various viral receptors and proteases, transcription factors, cytokines/chemokines, coagulation & angiogenesis associated proteins, and fibrosis markers. More importantly, drugs targeting G9a and its associated protein EZH2 are potent inhibitors of SARS-CoV-2 replication and reverse multi-omic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and COVID-19 patient PBMCs - with similar changes seen in multiorgan autopsy samples from COVID-19 patients. Altogether, we extend G9a function(s) beyond transcription to translational regulation during COVID-19 pathogenesis and show that targeting this master regulatory complex represents a new strategy (drug-class) that can be leveraged to combat emerging anti-viral resistance and infections.

2025-04-14 | PXD058743 | Pride

The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients

Project description:The RNA modification N6-methyladenosine (m6A) plays a key role in the life cycles of several RNA viruses. Whether this applies to SARS-CoV-2 and whether m6A affects the outcome of COVID-19 disease is still poorly explored. Here we report that the RNA demethylase FTO strongly affects both m6A marking of SARS-CoV-2 and COVID-19 severity. By m6A profiling of SARS-CoV-2, we confirmed in infected cultured cells and showed for the first time in vivo in hamsters that the regions encoding TRS_L and the nucleocapsid protein are multiply marked by m6A, preferentially within RRACH motifs that are specific to β-coronaviruses and well conserved across SARS-CoV-2 variants. In cells, downregulation of the m6A demethylase FTO, occurring upon SARS-CoV-2 infection, increased m6A marking of SARS-CoV-2 RNA and slightly promoted viral replication. In COVID-19 patients, a negative correlation was found between FTO expression and both SARS-CoV-2 expression and disease severity. FTO emerged as a classifier of disease severity and hence a potential stratifier of COVID-19 patients.

2023-04-26 | GSE201626 | GEO

Modelling SARS-CoV-2 Infection in Mice Using Lentiviral hACE2 Vectors Suggests Two Modes of Immune Responses to SARS-CoV-2 Infection

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of individuals worldwide, causing a severe global pandemic. Mice models are wildly used to investigate viral infection pathology, antiviral drugs, and vaccine development. However, since wild-type mice do not express human angiotensin-converting enzyme 2 (hACE2), which mediates SARS-CoV-2 entry into human cells, they are not susceptible to infection with SARS-CoV-2 and are not suitable to simulate symptomatic COVID-19 disease. HACE2 transgenic mice could provide an efficient model, but they are expensive, not always readily available and practically restricted to specific strain(s). Since additional models are needed to study the disease at varying genetic and immune backgrounds, there is a dearth of mouse models for SARS-CoV-2 infection. Here we report the application of lentiviral vectors to generate hACE2 expression in mouse lung epithelial cells (LET1) as well as in interferon receptor knock-out (IFNAR1-/-) mice. Lenti-hACE2 transduction supported SARS-CoV-2 replication both in vitro and in vivo, simulating mild acute lung disease1. Gene expression analysis revealed two modes of immune responses to SARS-CoV-2 infection: one in response to the exposure of mouse lungs to SARS-CoV-2 particles in the absence of productive viral replication, and the second in response to a productive infection. This approach expands our knowledge on the role of type-1 interferon signaling in COVID-19 disease, and can be further implemented for a range of COVID-19 studies and drug development.

2021-12-07 | GSE186167 | GEO

Enhancing Human ACE2 Expression in Mouse Models for Improved COVID-19 Research

Project description:Several humanized ACE2 (hACE2) mouse models have been developed for COVID-19 studies. Insertion of hACE2 at mouse Ace2 locus enables the utilization of endogenous promoter to drive its expression, better reflecting ACE2 abundance in various cell types and tissues. However, the relatively low expression of hACE2 in these mice may limit their fidelity in mimicking COVID-19 manifestations in humans and hinder their application in viral studies. In this study, we generated four hACE2 mouse models using different strategies for hACE2 expression. We found that the position of the β-globin intron within hACE2 cassette could have contrasting effects on hACE2 expression, with its placement downstream of hACE2 significantly increasing its transcription. Western blot analysis demonstrated that optimizing hACE2 codon usage further enhanced translation efficiency from all tested tissue. Consistent with elevated hACE2 expression, opt-hACE2 mice displayed more active immune response and severe COVID-19 phenotypes following SARS-CoV-2 challenging compared to other hACE2 mouse models. Thus, our study has elucidated the dual role of β-globin element in transgene expression, and highlighted that mice with optimized hACE2 codon preference could serve as a better model for SARS-CoV-2 studies.

2025-02-12 | GSE271163 | GEO

Infiltrating Monocytes Drive Cardiac Dysfunction in a Cardiomyocyte-Restricted Model of SARS-CoV-2 Infection

Project description:Cardiovascular manifestations of COVID-19 include myocardial injury, heart failure, and myocarditis and are associated with long-term disability and mortality. SARS-CoV-2 RNA and antigens are found in the myocardium of COVID-19 patients, and human cardiomyocytes are susceptible to infection in cell or organoid cultures. While these observations raise the possibility that cardiomyocyte infection may contribute to the cardiac sequelae of COVID-19, a causal relationship between cardiomyocyte infection and myocardial dysfunction and pathology has not been established. Here, we generated a mouse model of cardiomyocyte-restricted infection by selectively expressing human angiotensin converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, in cardiomyocytes. Inoculation of Myh6-Cre Rosa26LSL-hAce2 mice with SARS-CoV-2 resulted in viral replication within the heart, accumulation of macrophages, and moderate left ventricular (LV) systolic dysfunction. Cardiac pathology in this model was transient and resolved with viral clearance. Blockade of monocyte trafficking reduced myocardial viral replication and macrophage accumulation and suppressed the development of LV systolic dysfunction. These findings establish a mouse of model of SARS-CoV-2 cardiomyocyte infection that recapitulates features of cardiac dysfunctions of COVID-19 and suggests that both replication and resultant innate immune responses contribute to pathology

2023-12-31 | GSE239372 | GEO

IL-1β-driven NF-kB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2

Project description:Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice or an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor, inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1β-driven NF-B transcription of ACE2 appeared to be an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.

2024-12-31 | GSE284552 | GEO

m6A modification in SARS-CoV-2 virus regulates host cell innate immune response

Project description:It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlying molecular mechanism. RNA modification landscape of SARS-CoV-2 and its functional relevance to host cell innate immune response remain unknown. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigated m6A modification of SARS-CoV-2 gene in regulating host cell innate immune response. Our data showed that SARS-CoV-2 virus has m6A modification enriched in 3' region of the viral genome. We also found that host cell m6A methyltransferase METTL3 depletion reduced viral load in infected cells, decreased m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increased RIG-1 binding and subsequently enhanced downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in severe COVID-19 patients. These findings will aid to understand the COVID-19 pathogenesis and help in designing future studies of regulating innate immunity for COVID-19 treatment.

2021-04-27 | GSE167075 | GEO

Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion

Project description:The development of tractable animal models that faithfully reproduce COVID-19 pathogenesis would arguably be a major benefit. Infection of transgenic mice expressing the human version of the SARS-CoV-2 receptor (hACE2) by intranasal instillation of a liquid SARS-CoV-2 suspension under deep anesthesia results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the characterization of a novel COVID-19 mouse model based on an inhalation tower system that allows to expose unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction, but did not lead to fatal viral neuroinvasion. When compared to intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition and a transcriptional signature comparable to that observed in humans. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions.

2021-11-23 | GSE184657 | GEO

Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19.

Project description:Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19), with effective versus dysregulated responses influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross founder strains crossed to K18-hACE2 mice that confers high susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, early kinetics of type I interferon (IFN) responses, and a regulated proinflammatory response were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding antiviral immunity.

2023-06-07 | GSE231711 | GEO

Mapping of Functional SARS-CoV-2 Receptors in Human Lungs Establishes Differences in Variant Binding and SLC1A5 as a Viral Entry Modulator of hACE2

Project description:The COVID-19 pandemic is an infectious disease caused by SARS-CoV-2. The first step of SARS-CoV-2 infection is the recognition of angiotensin-converting enzyme 2 (hACE2) receptors by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Although the molecular and structural bases of the SARS-CoV-2-RBD/hACE2 interaction have been thoroughly investigated in vitro, the relationship between hACE2 expression and in vivo infection is less understood. Here, we developed an efficient SARS-CoV-2-RBD binding assay suitable for super resolution microscopy and simultaneous hACE2 immunodetection and mapped the correlation between hACE2 receptor abundance and SARS-CoV-2-RBD binding, both in vitro and in human lung biopsies. Next, we explored the specific proteome of SARS-CoV-2-RBD/hACE2 through a comparative mass spectrometry approach. We found that only a minority of hACE2 positive spots are actually SARS-CoV-2-RBD binding sites, and that the relationship between SARS-CoV-2-RBD binding and hACE2 presence is variable, suggesting the existence of additional factors. Indeed, we found several interactors that are involved in receptor localization and viral entry and characterized one of them: SLC1A5, an amino acid transporter. High-resolution receptor-binding studies showed that co-expression of membrane-bound SLC1A5 with hACE2 predicted SARS-CoV-2 binding and entry better than hACE2 expression alone. Accordingly, SLC1A5 depletion reduces SARS-CoV-2 binding and entry. Notably, the Omicron variant is more efficient in binding hACE2 sites, but equally sensitive to SLC1A5 downregulation. We propose a method for mapping functional SARS-CoV-2 receptors in vivo. We confirm the existence of hACE2 co-factors that may contribute to differential sensitivity of cells to infection.

2023-01-09 | PXD038005 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data