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Exon junction complex shapes the m6A epitranscriptome

Author

Listed:
  • Xin Yang

    (Boston Children’s Hospital
    Harvard Medical School)

  • Robinson Triboulet

    (Boston Children’s Hospital
    Harvard Medical School
    Twentyeight-Seven Therapeutics)

  • Qi Liu

    (Boston Children’s Hospital
    Harvard Medical School
    Rice Research Institute, Guangdong Academy of Agricultural Sciences
    Guangdong Key Laboratory of New Technology in Rice Breeding)

  • Erdem Sendinc

    (Boston Children’s Hospital
    Harvard Medical School)

  • Richard I. Gregory

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Medical School
    Harvard Stem Cell Institute)

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.

Suggested Citation

  • Xin Yang & Robinson Triboulet & Qi Liu & Erdem Sendinc & Richard I. Gregory, 2022. "Exon junction complex shapes the m6A epitranscriptome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35643-1
    DOI: 10.1038/s41467-022-35643-1
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    2. Zhiyuan Luo & Qilian Ma & Shan Sun & Ningning Li & Hongfeng Wang & Zheng Ying & Shengdong Ke, 2023. "Exon-intron boundary inhibits m6A deposition, enabling m6A distribution hallmark, longer mRNA half-life and flexible protein coding," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Xiaohua Xu & Chou-Wei Chang & Min Li & Kenneth Omabe & Nhung Le & Yi-Hsuan Chen & Feng Liang & Yilun Liu, 2023. "DNA replication initiation factor RECQ4 possesses a role in antagonizing DNA replication initiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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