GSE114019
m6A mRNA methylation controls the innate immune response to infection by targeting interferon ß
N6-methyladenosine (m6A), the most abundant mRNA modification, was shown to alter the life cycles of diverse DNA and RNA viruses. These effects were proposed to be mediated in a virus-specific manner, through dysregulated methylation of viral RNA. We use RNA-seq to systematically follow differences in gene expression in cells depleted of m6A machinery, compared to control cells, following human cytomegalovirus (HCMV) infection. We show that following viral infection or stimulation of cells with an inactivated virus, depletion of the m6A 'writer' protein METTL3  or 'reader' protein YTHDF2 leads to a dramatic increase in the induction of hundreds of interferon-stimulated genes (ISGs), which constitutes the first line of antiviral defense. Consequently, propagation of different viruses is markedly suppressed in an interferon (IFN)-signaling dependent manner. Furthermore, we used m6A-immunoprecipitation, followed by RNA-seq, to map m6A sites on human and HCMV transcripts, and found that the mRNA of IFNß, the central cytokine that drives the type I IFN response, is m6A modified, and is stabilized upon repression of METTL3 and YTHDF2. Overall design: mRNA-seq of total mRNA and m6A-immunoprecipitated mRNA from METTL3-depleted and control human fibroblasts, following HCMV infection.