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N 6 –methyladenosine (m 6 A) is the most abundant mRNA modification and plays crucial roles in diverse physiological processes. Utilizing 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 co-localize with EJC-suppressed splice sites, suggesting that exon architecture broadly determines local mRNA accessibility to regulatory complexes.

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