SARS-CoV-2 reshapes m6A methylation in long noncoding RNAs of human lung cells

TL;DR

This study shows that SARS-CoV-2 infection increases m6A methylation in certain long noncoding RNAs in human lung cells, potentially affecting immune responses.

Contribution

The paper introduces new insights into m6A methylation changes in lncRNAs during SARS-CoV-2 infection using machine learning analysis.

Findings

SARS-CoV-2 infection leads to increased m6A levels in 10 antiviral lncRNAs.

UCA1, GAS5, and NORAD show significant m6A changes, possibly affecting interferon signaling.

Methylated motifs in lncRNAs may destabilize structures and alter interactions.

Abstract

N6-Methyladenosine (m6A) is a key base modification that regulates RNA stability and translation during viral infection. While m6A methylation of host mRNAs has been studied in SARS-CoV-2-infected cells, its role in long noncoding RNAs (lncRNAs) is unknown. Here, we analyzed direct RNA sequencing (dRNA-seq) data from infected human lung cells (Calu-3) using a machine learning m6A detection framework. We observed a global increase in m6A levels across 10 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 m6A-dependent mechanisms.

Graphical Abstract

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