Exon junction complex shapes the m6A epitranscriptome

Xin Yang, Robinson Triboulet, Qi Liu, Erdem Sendinc and Richard I. Gregory ()
Additional contact information
Xin Yang: Boston Children’s Hospital
Robinson Triboulet: Boston Children’s Hospital
Qi Liu: Boston Children’s Hospital
Erdem Sendinc: Boston Children’s Hospital
Richard I. Gregory: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract N6-methyladenosine (m6A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m6A is highly enriched in the 3’ untranslated region (UTR) of a large subset of mRNAs to influence mRNA stability and/or translation. However, the mechanism responsible for the observed m6A distribution remains enigmatic. Here we find the exon junction complex shapes the m6A landscape by blocking METTL3-mediated m6A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m6A modification of short internal exons, and sites close to exon-exon junctions within mRNA. Reporter gene experiments further support the role of splicing and EIF4A3 deposition in controlling m6A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m6A mRNA modification are established and uncover a role of the EJC in shaping the m6A epitranscriptome.

Date: 2022
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DOI: 10.1038/s41467-022-35643-1

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