The mA methylome of SARS-CoV-2 in host cells.

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency because of its rapid spread and high mortality. The molecular mechanism of interaction between host and viral genomic RNA is yet unclear. We demonstrate herein that SARS-CoV-2 genomic RNA, as well as the negative-sense RNA, is dynamically N-methyladenosine (mA)-modified in human and monkey cells. Combined RIP-seq and miCLIP analyses identified a total of 8 mA sites at single-base resolution in the genome. Especially, epidemic strains with mutations at these identified mA sites have emerged worldwide, and formed a unique cluster in the US as indicated by phylogenetic analysis. Further functional experiments showed that mA methylation negatively regulates SARS-CoV-2 infection. SARS-CoV-2 infection also triggered a global increase in host mA methylome, exhibiting altered localization and motifs of mA methylation in mRNAs. Altogether, our results identify mA as a dynamic epitranscriptomic mark mediating the virus-host interaction.