m(6)A-mediated modulation coupled with transcriptional regulation shapes long noncoding RNA repertoire of the cGAS-STING signaling

The cGAS-STING signaling plays pivotal roles not only in host antiviral defense but also in various noninfectious contexts. Compared with protein-coding genes, much less was known about long noncoding RNAs involved in this pathway. Here, we performed an integrative study to elucidate the lncRNA repertoire and the mechanisms modulating lncRNA’s expression following cGAS-STING signaling activation. We uncovered a reliable set of 672 lncRNAs closely linked to cGAS-STING signaling activation (cs-lncRNA), which might be associated with type-I interferon response and infection-related phenotypes. The ChIP-seq analysis demonstrated that cs-lncRNA was strongly regulated at the transcriptional level. We further found N6-methyladenosine (m(6)A) regulatory machinery was indispensable for establishing cs-lncRNA repertoire via modulating m(6)A modification on cs-lncRNA transcripts and promoting the expression of signaling transduction key components, including IFNAR1. Loss of IFNAR1 led to the dysregulation of cs-lncRNAs resembled that of loss of an essential subunit of m(6)A writer METTL14. We also found m(6)A system affected transcriptional machinery to modulate cs-lncRNAs by targeting multiple crucial transcription factors. Inhibiting an m(6)A modification regulated transcription factor, EZH2, markedly enhanced the expression pattern of cs-lncRNAs. Taken together, our results uncovered the composition of the cs-lncRNAs and revealed m(6)A-mediated modulation coupled with transcriptional regulation significantly shaped cs-lncRNA repertoire.