Exon architecture controls mRNA m6A suppression and gene expression

N6-methyladenosine (m6A) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for m6A (MPm6A), we discover that m6A specificity is globally regulated by suppressors that prevent m6A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m6A suppressors that protect exon junction–proximal RNA within coding sequences from methylation and regulate mRNA stability through m6A suppression. EJC suppression of m6A underlies multiple global characteristics of mRNA m6A specificity, with the local range of EJC protection sufficient to suppress m6A 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. Description Methylation suppression Methylation of the N6 position of adenine (m6A) is a chemical tag for many messenger RNAs (mRNAs) added by m6A “writer” proteins. Tagged mRNAs are marked for regulation through m6A “reader” proteins, which bind methylated mRNAs and alter their expression. However, how the cell selects specific regions on mRNAs to be marked has remained unclear. He et al. identified a new function for the exon junction complex as an m6A “suppressor” that packages nearby mRNA and protects these regions from m6A marking. Exon architecture controls mRNA accessibility to m6A methylation, as well as potentially a broader set of regulatory complexes. —DJ Exon junction complexes are m6A suppressors that control global mRNA m6A specificity by protecting proximal RNA from methylation.

• Publication year

  2023

• Venue

  Science

• Publication date

  2023-01-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1126/science.abj9090PMID 36705538PMCID 9990141
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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