The m6A methylome of SARS-CoV-2 in host cells

Liu, June; Xu, Yixin; Li, Kai; Ye, Qing; Zhou, Hang; Sun, Hai; Li, Xiaoyu; Liu, Yu; Deng, Yong Qiang; Li, Rui Ting; Cheng, Miao; He, Bo; Zhou, Jia; Li, Xiao Feng; Wu, Aiping; Yi, Chengqi; Cheng, Qi

doi:10.1038/s41422-020-00465-7

Cited by 106 publications

(205 citation statements)

References 66 publications

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“…Several of these regions overlap with the meRIP-seq peaks identified in our study but not with the single low-confidence site predicted by comparison of DRS data sets prepared in the presence or absence of a selective METTL3 small molecule inhibitor. A different study implicating METTL3 in the m 6 A modification of viral RNAs and in regulation of host responses during SARS-CoV-2 infection also appeared while our manuscript was in revision (Liu et al 2021).…”

Section: Discussionmentioning

confidence: 87%

“…It is notable that several peaks were placed in regions represented by the genome length transcripts (gRNA) only, suggesting that both gRNA and subgenomic RNAs (sgRNAs) are m 6 A-modified. We also compared the SARS-CoV-2 peak regions with the meRIP-seq and miCLIP data from SARS-CoV-2infected Vero and Huh7 cells reported by Liu and colleagues (Liu et al 2021). Despite the differences in cell lines and infection conditions, 10 of the meRIP-seq peak regions were found to overlap between the studies and four of our meRIP-seq peaks overlapped with sites identified by miCLIP (Supplemental Fig.…”

Section: β-Coronavirus Rnas Are M 6 A-modifiedmentioning

confidence: 79%

“…We have also shown by antibody-based RNA capture (meRIP-seq) that viral mRNAs are m 6 A-modified over multiple regions that contain consensus DRACH m 6 A acceptor motifs. Recently, Liu et al (2021) reported eight high-confidence m 6 A sites on SARS-CoV-2 RNAs using a combination of meRIPseq and miCLIP. Several of these regions overlap with the meRIP-seq peaks identified in our study but not with the single low-confidence site predicted by comparison of DRS data sets prepared in the presence or absence of a selective METTL3 small molecule inhibitor.…”

Section: Discussionmentioning

confidence: 99%

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Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

et al. 2021

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N 6 -methyladenosine (m 6 A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of m 6 A by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also m 6 A-modified. How the cellular m 6 A modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown. Here we show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human β-coronavirus HCoV-OC43, can be suppressed by depletion of METTL3 or cytoplasmic m 6 A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 inhibitor. Reduction of infectious titer correlates with decreased synthesis of viral RNAs and the essential nucleocapsid (N) protein. Sites of m 6 A modification on genomic and subgenomic RNAs of both viruses were mapped by methylated RNA immunoprecipitation sequencing (meRIP-seq). Levels of host factors involved in m 6 A installation, removal, and recognition were unchanged by HCoV-OC43 infection; however, nuclear localization of METTL3 and cytoplasmic m 6 A readers YTHDF1 and YTHDF2 increased. This establishes that coronavirus RNAs are m 6 A-modified and host m 6 A pathway components control β-coronavirus replication. Moreover, it illustrates the therapeutic potential of targeting the m 6 A pathway to restrict coronavirus reproduction.

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Section: Discussionmentioning

confidence: 87%

Section: β-Coronavirus Rnas Are M 6 A-modifiedmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

et al. 2021

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“…However, these m 6 A modifications negatively modulate SARS-CoV-2 life cycle. The viral replication is dramatically increased upon knockdown of METTL3 and METTL14 (92). This study suggests that m 6 A decoration may be a negative regulator for SARS-CoV-2 infection, providing a potential therapeutic avenue for the development of vaccine and antiviral drugs of SARS-CoV-2.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 75%

Emerging Perspectives of RNA N6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases

Tang

Wei

et al. 2021

Front. Immunol.

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N6-methyladenosine (m6A) modification, the addition of a methylation decoration at the position of N6 of adenosine, is one of the most prevalent modifications among the over 100 known chemical modifications of RNA. Numerous studies have recently characterized that RNA m6A modification functions as a critical post-transcriptional regulator of gene expression through modulating various aspects of RNA metabolism. In this review, we will illustrate the current perspectives on the biological process of m6A methylation. Then we will further summarize the vital modulatory effects of m6A modification on immunity, viral infection, and autoinflammatory disorders. Recent studies suggest that m6A decoration plays an important role in immunity, viral infection, and autoimmune diseases, thereby providing promising biomarkers and therapeutic targets for viral infection and autoimmune disorders.

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“…Remarkably, the m 6 A writer RBM15/RBM15B was identified to interact with NRC10 in Huh7 cells (Figure 5B). A recent study demonstrates that the m 6 A is prevalent in the negative-sense RNA of SARS-CoV-2 71 . In Calu-3 cells, SAMD9 was identified to interact with NRC10 (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

Mapping the host protein interactome of non-coding regions in SARS-CoV-2 genome

Jiang

Xiao

Liao

et al. 2021

Preprint

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A deep understanding of SARS-CoV-2-host interactions is crucial to the development of effective therapeutics. The role of non-coding regions of viral RNA (ncrRNAs) has not been scrutinized. We developed a method using MS2 affinity purification coupled with liquid chromatography-mass spectrometry (MAMS) to systematically map the interactome of SARS-CoV-2 ncrRNA in different human cell lines. Integration of the results defined the core and cell-type-specific ncrRNA-host protein interactomes. The majority of ncrRNA-binding proteins were involved in RNA biogenesis, protein translation, viral infection, and stress response. The 5′ UTR interactome is enriched with proteins in the snRNP family and is a target for the regulation of viral replication and transcription. The 3′ UTR interactome is enriched with proteins involved in the cytoplasmic RNP granule (stress granule) and translation regulation. We show that the ORF10 is likely to be a part of 3′ UTR. Intriguingly, the interactions between negative-sense ncrRNAs and host proteins, such as translation initiation factors and antiviral factors, suggest a pathological role of negative-sense ncrRNAs. Moreover, the cell-type-specific interactions between ncrRNAs and mitochondria may explain the differences of cell lines in viral susceptibility. Our study unveils a comprehensive landscape of the functional SARS-CoV-2 ncrRNA-host protein interactome, providing a new perspective on virus-host interactions and the design of future therapeutics.

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The m6A methylome of SARS-CoV-2 in host cells

Cited by 106 publications

References 66 publications

Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Emerging Perspectives of RNA N6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases

Mapping the host protein interactome of non-coding regions in SARS-CoV-2 genome

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The m6A methylome of SARS-CoV-2 in host cells

Cited by 106 publications

References 66 publications

Targeting the m6A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Targeting the m6A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Emerging Perspectives of RNA N6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases

Mapping the host protein interactome of non-coding regions in SARS-CoV-2 genome

Contact Info

Product

Resources

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Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication

Targeting the m⁶A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication