m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development.

摘要: Summary N6-methyladenosine (m6A) is the most abundant RNA modification, but little known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of m6A writer METTL3 murine fetal liver resulted failure and perinatal lethality. Loss activated an aberrant innate immune response, mediated by formation endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly modified their native state, characterized low folding energies, predominantly protein coding. We identified coinciding activation pattern recognition receptor pathways normally tasked with detection foreign dsRNAs. Disruption response via abrogation downstream Mavs or Rnasel signaling partially rescued observed defects METTL3-deficient cells in vitro in vivo. Our results suggest modification protects against dsRNA a deleterious during