m6A depletion attenuates the macrophage type I interferon response [RNA-Seq]

Post-transcriptional regulation of mRNA is important for inflammatory gene expression that supports the defense against viral pathogens. N-6 methyladenosine (m6A) deposition on mRNA by METTL3 constitutes one such post-transcriptional event which facilitates a cascade of downstream regulation via RNA decay and translation.

We were surprised to find that in both THP1-derived and peripheral blood macrophages, m6A depletion with the METTL3 inhibitor STM2457 leads to a defective type I interferon response and enhanced proliferation of the human coronavirus OC43. Using TimeLapse-seq to simultaneously measure changes in abundance, RNA decay and transcription, we find that STM2457 downregulates the interferon response at the receptor level and via reduction in the potency of the first wave of transcription.