SARS-CoV-2 reshapes mA methylation in long non-coding RNAs of human lung cells

N-Methyladenosine (mA) is a key base modification that regulates RNA stability and translation during viral infection. While mA methylation of host mRNAs has been studied in SARS-CoV-2-infected cells, its role in long non-coding RNAs (lncRNAs) is unknown. Here, we analyzed direct RNA sequencing (dRNA-seq) data from infected human lung cells (Calu-3) using a machine learning mA detection framework. We observed a global increase in mA levels across ten antiviral response- associated lncRNAs, with UCA1, GAS5, and NORAD--regulators of interferon (IFN) signaling-- showing the most pronounced changes. This might, in part, explain the attenuated IFN expression observed in infected cells. We identified methylated DRACH motifs in predicted lncRNA duplex-forming regions, which may favor Hoogsteen base-pairing, which destabilize secondary structures and target interaction sites. These results provide new perspectives on how SARS-CoV-2 could impact lncRNAs to modulate host immunity and viral persistence through mA-dependent mechanisms. In BriefPeter et al. show that SARS-CoV-2 infection alters mA methylation of host lncRNAs by analysis of direct RNA sequencing data with machine learning. Key immune-regulatory lncRNAs show mA alterations in RNA pairing regions, suggesting a novel mechanism by which mA may modulate antiviral responses and promote viral persistence. HighlightsO_LIDirect RNA-seq and machine learning reveal mA changes in lncRNAs C_LIO_LISARS-CoV-2 infection changes mA patterns in antiviral response-associated lncRNAs C_LIO_LILncRNAs UCA1, GAS5, and NORAD exhibit pronounced mA remodeling upon infection C_LIO_LImA sites overlap RNA duplex-forming regions in immune-regulatory lncRNAs C_LIO_LImA may impact lncRNA duplexes via Hoogsteen pairing C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/658496v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@eb2e28org.highwire.dtl.DTLVardef@236149org.highwire.dtl.DTLVardef@c82cd3org.highwire.dtl.DTLVardef@1f70f9e_HPS_FORMAT_FIGEXP M_FIG C_FIG