A recent study published in Cell Death Discovery 6 A) methylation in coronavirus disease 2019 (COVID-19).
Study: m6A methylation: a potential key player in understanding and treating COVID-2019 infection . Image Credit: felipe caparros/Shutterstock.com Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, belongs to the Coronaviridae family and is closely related to SARS-CoV and middle-east respiratory syndrome (MERS)-CoV.
To date, COVID-19 has caused more than 769.7 million infections and 6.9 million deaths worldwide. m6 A is a common ribonucleic acid (RNA) modification and plays crucial roles in several biological processes.
Recent evidence suggests that m6 A methylation is associated with viral infections and impacts host cellular functions. Besides, it can also influence the life cycle and pathogenicity of viruses.
As such, understanding the role of m6 A methylation during SARS-CoV-2 infection can help inform COVID-19 prevention and treatment. In the present study, the authors reviewed available evidence on m6 A methylation and its role in COVID-19.
Overview of m6 A
m6 A methylation is highly enriched in the stop codons, long internal exons, and 3’-untranslated regions. It is catalyzed by methyltransferase-like 14 (METTL14) and METTL3. Besides, other proteins, including the WT1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15), have been implicated in m6 A methylation.
m6 A readers are proteins recognizing and binding to m6 A-modified RNA, such as insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), YTH N6-methyladenosine RNA-binding protein F1 (YTHDF1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), YTHDF2, YTHDF3, YTH N6-methyladenosine RNA-binding protein C1 (YTHDC1), and YTHDC2. Demethylases are m6 A erasers that reverse the m6 A modification, such as AlkB homolog 5 RNA demethylase (ALKBH5).
COVID-19 and m6 A
Evidence suggests that m6 A modification is vital for SARS-CoV-2 transmission and pathogenicity. One study revealed the de-regulation of m6 A modification in SARS-CoV-2-infected host cells. Another study reported higher m6 A levels in SARS-CoV-2-infected Calu-6 cells and Vero cells.
Further, m6 A downregulation was observed in leucocytes from infected patients. Significant downregulation of METTL3 was observed in the lung tissues of severe COVID-19 patients relative to healthy individuals.
One study observed elevated expression of HNRNPC, WTAP, fragile X messenger ribonucleoprotein 1 (FMR1), RBM15, heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), YTHDF3, YTHDC1, and ELAV-like RNA-binding protein 1 (ELAVL1) in COVID-19 patients. In contrast, the expression of insulin-like growth factor-binding protein 2 (IGFBP2), IGFB2BP1, and RBM15B was substantially reduced.
SARS-CoV-2 infection could alter the epigenetic transcriptome of m6 A in lymphocytes and enhance m6 A modification of RBM15 to regulate immune responses. A study revealed the downregulation of METTL3 in host cells upon SARS-CoV-2 infection, decreasing m6 A levels in host and viral genes and enhancing the expression of downstream inflammatory genes and innate immune responses.
Impact of m6 A modification on SARS-CoV-2 evolution
One study explored methylation profiles in monkey and human cells infected with SARS-CoV-2 and revealed the dynamic distribution patterns. It also observed widespread occurrence of the modification on negative-strand RNAs. Moreover, the investigators used more precise techniques and demonstrated eight m6 A modification sites at single-base resolution.
Functional analyses indicated that METTL3, METTL14, and ALKBH5 regulated SARS-CoV-2 replication and that a reduction in m6 A reader, YTHDF2, promoted replication and infectivity. Moreover, SARS-CoV-2 can use host enzymes for methylation to adapt its DRACH sequence (D = A/G/U, R = A/G, H = A/C/U) and evade interferons.
m6 A and COVID-19 diagnosis and treatment
The mechanisms underlying m6 A methylation could be leveraged to develop prophylactic and therapeutic approaches for COVID-19. For instance, a model designed to predict COVID-19 risk by screening m6 A-associated genes was successful.
Similarly, another study reported highly accurate prediction of COVID-19 occurrence using random forest models. Thus, prediction models are expected to reveal the early onset and progression of COVID-19.
m6 A-related genes can be modified to reduce SARS-CoV-2 virulence. That is, knocking down YTHDF2, METTL14, and METTL3 elevated SARS-CoV-2 replication, whereas ALKBH5 knockdown repressed it, suggesting that drugs against m6 A regulators could be effective in COVID-19 treatment.
There are reports of small molecules targeting m6 A regulators with antagonistic effects against other viruses. However, additional research is warranted to screen m6 A-related small molecules targeting SARS-CoV-2.
Concluding remarks
Although m6 A modification has been implicated as critical in COVID-19, further investigations are necessary to unravel the underlying regulatory mechanisms. Additionally, research on m6 A-related small molecules targeting SARS-CoV-2 is warranted. Overall, an increased understanding of the role of m6 A modifications in COVID-19 may result in the development of novel therapies in the future.
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