m6A-mediated modulation coupled with transcriptional regulation shapes long noncoding RNA repertoire of the cGAS-STING signaling

Jinyi Song; Lele Zhang; Chenhui Li; Munire Maimaiti; Jing Sun; Jiameng Hu; Lu Li; Xiang Zhang; Chen Wang; Haiyang Hu

doi:10.1016/j.csbj.2022.04.002

m⁶A-mediated modulation coupled with transcriptional regulation shapes long noncoding RNA repertoire of the cGAS-STING signaling

Comput Struct Biotechnol J. 2022 Apr 9:20:1785-1797. doi: 10.1016/j.csbj.2022.04.002. eCollection 2022.

Authors

Jinyi Song¹, Lele Zhang², Chenhui Li¹, Munire Maimaiti¹, Jing Sun¹, Jiameng Hu¹, Lu Li¹, Xiang Zhang¹, Chen Wang¹, Haiyang Hu¹

Affiliations

¹ State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, China.
² Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

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 (m⁶A) regulatory machinery was indispensable for establishing cs-lncRNA repertoire via modulating m⁶A 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 m⁶A writer METTL14. We also found m⁶A system affected transcriptional machinery to modulate cs-lncRNAs by targeting multiple crucial transcription factors. Inhibiting an m⁶A 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 m⁶A-mediated modulation coupled with transcriptional regulation significantly shaped cs-lncRNA repertoire.

Keywords: N6-methyladenosine (m6A); Transcription factor; Transcriptional regulation; cGAS-STING signaling; lncRNA.