WTAP, transcriptionally regulated by p65, promotes inflammation through m6A modification and phase separation

Emerging evidence has linked dysregulation of N 6 -methyladenosine (m 6 A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m 6 A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m 6 A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of “writer” complex to nuclear speckles and the deposition of m 6 A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m 6 A writer complex by targeting the phase separation of WTAP to reduce the global m 6 A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.