Posttranscriptional modification of viral and cellular RNA by N 6 -methyladenosine (m 6 A) plays an important role in regulating the replication of many viruses and the cellular immune response to infection. We therefore sought to define the epitranscriptomic m 6 A profile of human lung epithelial cells infected with SARS-CoV-2.

N6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification that plays an important role in determining transcript fate. Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused the global pandemic of coronavirus disease 2019 (COVID-19) and the virus has been extensively studied. However, how m6A modification of host cell RNAs change during SARS-CoV-2 infection has not been reported. Here we define the epitranscriptomic m6A profile of SARS-CoV-2-infected human lung epithelial cells compared to uninfected controls. Biological pathway analyses revealed that differentially methylated transcripts were significantly associated with cancer-related pathways, protein processing in the endoplasmic reticulum, cell death and proliferation. Upstream regulators predicted to be associated with the proteins encoded by differentially methylated mRNAs include proteins involved in the type I interferon response, inflammation, and cytokine signaling. These data suggest that m6A modification of cellular RNA is an important mechanism of regulating host gene expression during SARS-CoV-2 infection of lung epithelial cells.