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.