Exon architecture controls mRNA m 6 A suppression and gene expression.

-methyladenosine (mA) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for mA (MPmA), we discover that mA specificity is globally regulated by suppressors that prevent mA deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as mA suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through mA suppression. EJC suppression of mA underlies multiple global characteristics of mRNA mA specificity, with the local range of EJC protection sufficient to suppress mA deposition in average-length internal exons but not in long internal and terminal exons. EJC-suppressed methylation sites colocalize with EJC-suppressed splice sites, which suggests that exon architecture broadly determines local mRNA accessibility to regulatory complexes.