Phase transition of WTAP regulates m6A modification of interferon-stimulated genes

Abstract

AbstractN6-methyladenosine (m6A) is the most prevalent modification of mRNA which controls diverse physiological processes. Although m6A modification is reported to regulate type I interferon (IFN) responses by targeting the mRNA of IFN-β and the interferon stimulated genes (ISGs), the detailed mechanism of how m6A methyltransferase complex (MTC) responses quickly to conduct the modification on nascent mRNA co-transcriptionally during IFN-β stimulation remains largely unclear. Here, we demonstrate that WTAP, the adaptor protein of m6A MTC, goes through dephosphorylation regulated phase transition from aggregates to liquid droplets under IFN-β stimulation. Phase transition of WTAP mediates the m6A modification of a subset of ISGs mRNA to restrict their expression. In mechanism, we found that formation of aggregates prevents WTAP from binding on the promoter region of ISGs or conducting m6A modification on mRNA in untreated cells. while IFN-β induced WTAP droplets interacts with nucleus-translocated transcriptional factor STAT1 and recruits MTC on the promoter region of ISGs, directing the co-transcriptional m6A modification on ISGs mRNA. Collectively, our findings reveal a novel regulatory role of WTAP phase transition under viral infection to orchestrate dynamic m6A modification with the cooperation of transcriptional factors and MTC, and precisely manipulate signaling pathway.