Epitranscriptomic m6A profile of SARS-CoV-2-infected human lung epithelial cells

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Abstract The COVID-19 pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in global health and economic crises. To develop effective vaccines and antivirals to prevent and control SARS-CoV-2 or other coronavirus infections, it is critical to understand the regulatory mechanisms of SARS-CoV-2 genome replication in host cells. In this R21 project, we will use novel epitranscriptomic technologies to investigate SARS-CoV-2 replication in human lung epithelial cells. N6-methyladenosine (m6A) modifications of many viruses play a major role in epitranscriptomic regulation of viral replication, gene expression, and immune evasion. However, it is unclear whether and how m6A modifications of the SARS-CoV-2 genome and cellular genes affect viral replication and pathogenicity. Our preliminary studies showed that SARS-CoV-2 infection of human lung epithelial cells upregulated m6A levels in cellular RNA. Our bioinformatic analysis of 13,699 full-length SARS- CoV-2 genome sequences predicts multiple m6A modification sites that are highly conserved among SARS-CoV-2 isolates worldwide. Thus, we hypothesize that m6A modifications of the SARS-CoV-2 genome and cellular genes enhance viral replication in cells through epitranscriptomic regulation. We propose two specific aims to test this hypothesis. Aim 1. To investigate the m6A epitranscriptomic profile of SARS-CoV-2-infected lung epithelial cells; Aim 2. To map m6A sites on the SARS-CoV-2 genome and to identify critical sites for viral replication. Defining epitranscriptomic m6A profile of SARS-CoV-2-infected cells has significant implications in understanding the COVID-19 pathogenesis and identifying novel drug targets.