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

N⁶-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.