The risk of COVID-19 can be predicted by a nomogram based on m6A-related genes

Lu, Lingling; Li, Yijing; Ao, Xiulan; Huang, Jiaofeng; Liu, Bang; Wu, Liqing; Li, Dongliang

doi:10.1016/j.meegid.2022.105389

Cited by 3 publications

(4 citation statements)

References 48 publications

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“…As an m 6 A writer, METTL3 interacts with SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) in the host to facilitate SARS-CoV-2 RNA m 6 A modification and viral replication 35 . Similarly, an elevated level of METTL3 and m 6 A readers, such as RBM15B, IGF2BP1, hnRNPA1, coupled with a decrease in m 6 A demethylase (FTO, ALKBH5) expression was reported in SARS-CoV-2 infected cell lines [33][34][35][36] and clinical isolates from severe COVID-19 patients [37][38][39][40] . Correspondingly, we identified by ChaC most of m 6 A regulators (e.g., writers or readers) as the COVID-19 phenotypic interactors and showed that G9a inhibition reversed the SARS-CoV-2induced m 6 A landscape (Figure 4b-4c); thus, via the METTL3-m 6 A axis, G9a regulates select SARS-CoV-2hijacked translation pathways.…”

Section: Discussionmentioning

confidence: 69%

“…writer) stabilizes mRNA transcripts by introducing m 6 A to promote translation 74,75 . In addition, SARS-CoV-2 infection increases expression of m 6 A regulators, including METTL3, and induces COVID-19 characteristic m 6 A landscapes in both virus and the host cells or patients, wherein the m 6 A modification was implicated in viral replication and dysregulation of host immune response [33][34][35][36][37][38][39][40][76][77][78] . Similarly, we showed that, in ET macrophages, G9a and METTL3 co-upregulated translation of certain m 6 A-modified mRNAs associated with sepsis and ARDS.…”

Section: G9a Promotes Sars-cov-2/m 6 A-coregulated Translation For Co...mentioning

confidence: 99%

“…Specifically, in COVID-19 related samples, G9a-interacting translation regulators included the N 6 methyladenosine (m 6 A) RNA methylase METTL3, 31,32 the ribosomal (r)RNA methylase fibrillarin (FBL), and another histone methyltransferase Ezh2. METTL3 is implicated in viral m 6 A RNA modification and SARS-CoV2 dysregulated host immune response [33][34][35][36] , and elevated m 6 A levels were found associated with severe clinical outcomes and mortality of COVID19 patients [37][38][39][40] . SARS-CoV-2 can escape the host cell innate immune response by mimicking the host mRNA capping machinery and 2′-O methylation (2′-O-Me), the most prevalent modification in rRNA; FBL is the only known methyltransferase that catalyzes site-specific 2′-O-Me of rRNA.…”

Section: Introductionmentioning

confidence: 99%

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Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Muneer,

Xie,

Xie

et al. 2024

Preprint

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By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N6-methyladenosine (m6A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m6A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

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Section: Discussionmentioning

confidence: 69%

Section: G9a Promotes Sars-cov-2/m 6 A-coregulated Translation For Co...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Muneer,

Xie,

Xie

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, a study by Li et al showed that the m 6 A methylation gene METTL3 was significantly downregulated and inflammatory genes were upregulated in lung tissues of patients with severe COVID-2019 than in those of healthy individuals [ 16 ]. Additionally, Lu et al analyzed the expression of 9 writers, 15 readers, and 2 erasers for m 6 A modification in healthy individuals and COVID-2019 patients and observed that the expression of WTAP, RBM15, HNRNPC, YTHDC1, FMR1, HNRNPA2B1, ELAVL1, and YTHDF3 was markedly higher but the expression of RBM15B, IGFBP2, and IGF2BP1 was substantially poorer in COVID-2019 patients than in healthy individuals, illustrating that the above targets may be associated with the regulation of m 6 A on COVID-2019 infection [ 37 ] (Fig. 1 ).…”

Section: A and Covid-2019 Infectionmentioning

confidence: 99%

m6A methylation: a potential key player in understanding and treating COVID-2019 infection

Qian,

Zhou,

Duan

et al. 2023

Cell Death Discov.

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Since its discovery in 2019, coronavirus disease 2019 (COVID-2019) spans a wide clinical spectrum from the asymptomatic stage, mild infection, to severe pneumonia. In patients with COVID-2019, factors such as advanced age, diabetes, or hypertension are associated with a significantly increased risk of severe diseases and death. Of note, the mechanisms underlying differences in the risk and symptoms of COVID-2019 among different populations are still poorly characterized. Accordingly, it is imperative to elucidate potential pathophysiological mechanisms and develop targeted therapeutic approaches for COVID-2019 infection. N6-methyladenosine (m6A) is one of the most common modifications in mammalian RNA transcripts and is widely found in messenger RNAs and some non-coding RNAs. It has been reported that m6A methylation modifications are present in viral RNA transcripts, which are of great significance for the regulation of the viral life cycle. Furthermore, m6A methylation has recently been found to be strongly associated with COVID-2019 infection. Therefore, this article reviews recent advances in studies related to the role of m6A methylation in COVID-2019 infection.

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Emerging role of N6-methyladenosine RNA modification in regulation of SARS-CoV-2 infection and virus-host interactions

Liu,

Chen,

Guo

et al. 2024

Biomedicine & Pharmacotherapy

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The risk of COVID-19 can be predicted by a nomogram based on m6A-related genes

Cited by 3 publications

References 48 publications

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

m6A methylation: a potential key player in understanding and treating COVID-2019 infection

Emerging role of N6-methyladenosine RNA modification in regulation of SARS-CoV-2 infection and virus-host interactions

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