Long noncoding RNA <i>CHROMR</i> regulates antiviral immunity in humans

Abstract

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA <i>CHROMR</i> is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. <i>CHROMR</i> depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that <i>CHROMR</i> sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, <i>CHROMR</i> expression is essential to restrict viral infection of macrophages. Our findings identify <i>CHROMR</i> as a key arbitrator of antiviral innate immune signaling in humans.