Exon architecture controls mRNA m 6 A suppression and gene expression

N 6 -methyladenosine (m 6 A) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for m 6 A (MPm 6 A), we discover that m 6 A specificity is globally regulated by suppressors that prevent m 6 A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m 6 A suppressors that protect exon junction–proximal RNA within coding sequences from methylation and regulate mRNA stability through m 6 A suppression. EJC suppression of m 6 A underlies multiple global characteristics of mRNA m 6 A specificity, with the local range of EJC protection sufficient to suppress m 6 A 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.