Study explores the role of N6-methyladensoine methylation and COVID-19

A recent study published in Cell Death Discovery summarized the recent advances in the role of N6-methyladenosine (m⁶A) methylation in coronavirus disease 2019 (COVID-19).

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. m⁶A is a common ribonucleic acid (RNA) modification and plays crucial roles in several biological processes.

Recent evidence suggests that m⁶A 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 m⁶A methylation during SARS-CoV-2 infection can help inform COVID-19 prevention and treatment. In the present study, the authors reviewed available evidence on m⁶A methylation and its role in COVID-19.

Overview of m⁶A

m⁶A 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 m⁶A methylation.

m⁶A readers are proteins recognizing and binding to m⁶A-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 m⁶A erasers that reverse the m⁶A modification, such as AlkB homolog 5 RNA demethylase (ALKBH5).

COVID-19 and m⁶A

Evidence suggests that m⁶A modification is vital for SARS-CoV-2 transmission and pathogenicity. One study revealed the de-regulation of m⁶A modification in SARS-CoV-2-infected host cells. Another study reported higher m⁶A levels in SARS-CoV-2-infected Calu-6 cells and Vero cells.

Further, m⁶A 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 m⁶A in lymphocytes and enhance m⁶A modification of RBM15 to regulate immune responses. A study revealed the downregulation of METTL3 in host cells upon SARS-CoV-2 infection, decreasing m⁶A levels in host and viral genes and enhancing the expression of downstream inflammatory genes and innate immune responses.

Impact of m⁶A 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 m⁶A modification sites at single-base resolution.

Functional analyses indicated that METTL3, METTL14, and ALKBH5 regulated SARS-CoV-2 replication and that a reduction in m⁶A 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.

m⁶A and COVID-19 diagnosis and treatment

The mechanisms underlying m⁶A 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 m⁶A-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.

m⁶A-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 m⁶A regulators could be effective in COVID-19 treatment.

There are reports of small molecules targeting m⁶A regulators with antagonistic effects against other viruses. However, additional research is warranted to screen m⁶A-related small molecules targeting SARS-CoV-2.

Concluding remarks

Although m⁶A modification has been implicated as critical in COVID-19, further investigations are necessary to unravel the underlying regulatory mechanisms. Additionally, research on m⁶A-related small molecules targeting SARS-CoV-2 is warranted. Overall, an increased understanding of the role of m⁶A modifications in COVID-19 may result in the development of novel therapies in the future.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.