M6A modification in SARS-CoV-2 virus regulates host cell innate immune response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA702920 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13743905_1.fastq.gz | Fastqsanger.gz | |||
| SRR13743905_2.fastq.gz | Fastqsanger.gz | |||
| SRR13743906_1.fastq.gz | Fastqsanger.gz | |||
| SRR13743906_2.fastq.gz | Fastqsanger.gz | |||
| SRR13743907_1.fastq.gz | Fastqsanger.gz |
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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
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
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.
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Project description:COVID-19 pandemic caused by SARS-CoV-2 is far from getting over because of the emergence of different SARS-CoV-2 variants even though vaccination against SARS-CoV-2 is ongoing. Variant specific mechanistic understanding of host-viral interaction will be required to design novel anti-viral therapeutics. N6-methyladenosine modification (m6A) which is one of the abundant cellular RNA modifications regulates key processes in RNA metabolism during stress response. We observed different SARS-CoV-2 variants during infection causes global loss of m6A in cellular RNA whereas m6A modification was detected abundantly in viral RNA. The loss of m6A in cellular RNAs was more drastic in B.1 and B1.1.7 strains and the main m6A methyltransferase METTL3 shows cytoplasmic localization post-infection. In B1.351 variant effect on METTL3 localization and loss of m6A was less pronounced compared to B.1 and B1.1.7 variants. Gene expression profile suggested changes in RNA catabolism-related pathways including key genes related to m6A readers and erasers during SARS-CoV-2 infection. Genes with m6A peaks were more susceptible to down-regulation during viral infection. Inhibition of export protein XPO1 during infection results in restoration of METTL3 nuclear localization and reduction in viral infection in cell culture suggesting XPO1 inhibition could be an effective therapeutic option for SARS-CoV-2.
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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
Project description:In this study we performed MeRIP-Seq to study N6-methyl adenosine (m6A) and and N6,2′ -O-dimethyladenosine (m6Am) modification of mRNA. We investigated the effect of the microbiota on the transcriptome and epitranscriptomic modifications in murine liver and cecum. We compared m6A/m modification profiles in cecum of conventionally raised (CONV) and germ-free (GF) mice. We additionally included GF mice colonised with the flora of CONV mice for four weeks (ex-GF), for which show that they exhibit similar patterns of the most abundant genera of gut bacteria as CONV mice. We added mice treated with several antibiotics to deplete the gut flora (abx)and vancomycin treated mice in which the genera Akkermansia, Escherichia/Shigella and Lactobacillus were enriched. Furthermore, we included GF mice colonised with the commensal bacterium Akkermansia muciniphila (Am), Lactobacillus plantarum (Lp) and Escherichia coli Nissle (Ec) and analysed their m6A/m modification profiles. In addition, we analysed changes in m6A/m- modified liver RNA for CONV, GF, and Am, Lp and Ec mice.
2020-02-12 | E-MTAB-6560 | biostudies-arrayexpress
Project description:To further investigate the underlying mechanisms of severe acute respiratory syndrome (SARS) pathogenesis and evaluate the therapeutic efficacy of potential drugs and vaccines it is necessary to use an animal model that is highly representative of the human condition in terms of respiratory anatomy, physiology and clinical sequelae. The ferret, Mustela putorius furo, supports SARS-CoV replication and displays many of the symptoms and pathological features seen in SARS-CoV-infected humans. We have recently established a SARS-CoV infection-challenge ferret platform for use in evaluating potential therapeutics to treat SARS. The main objective of the current study was to extend our previous results and identify early host immune responses upon infection and determine immune correlates of protection upon challenge with SARS-CoV in ferrets. Keywords: time course This study is a simple time course (58 day) examination of host responses in 35 SARS-CoV (TOR2) infected ferrets with the addition of a challenge inoculation of SARS CoV (TOR2) at day 29 post infection. Three mock-infected ferrets are included as negative controls. Due to the unavailability of ferret microarrays, Affymetrix Canine 2.0 oligonucleotide arrays were chosen following sequence analysis of our ferret cDNA library (~5000 clones) and demonstration of high levels of homology (>80%) between dog and ferret.
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Project description:Targeting G9a Regulated m6A Modification Pathway to Hinder SARS-CoV-2 Replication
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Project description:N6-methyl-adenosine (m6A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the evolutionary conservation and function of m6A by mapping the m6A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m6A modification, including transcripts encoding core pluripotency transcription factors. m6A is enriched over 3M-bM-^@M-^Y untranslated regions at defined sequence motifs, and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m6A methylases, led to m6A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESCM-bM-^@M-^Ys exit from self-renewal towards differentiation into several lineages in vitro and in vivo. Thus, m6A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages. Examing m6A modification differences in two different cell types
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2022-12-31 | E-MTAB-11411 | biostudies-arrayexpress