Exon junction complex shapes the m6A epitranscriptome

Xin Yang; Robinson Triboulet; Qi Liu; Erdem Sendinc; Richard I Gregory

doi:10.1038/s41467-022-35643-1

Exon junction complex shapes the m⁶A epitranscriptome

Nat Commun. 2022 Dec 23;13(1):7904. doi: 10.1038/s41467-022-35643-1.

Authors

Xin Yang^{1

2}, Robinson Triboulet^{1

2

3}, Qi Liu^{1

2

4

5}, Erdem Sendinc^{1

2}, Richard I Gregory^{6

7

8

9

10}

Affiliations

¹ Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.
² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
³ Twentyeight-Seven Therapeutics, Watertown, MA, 02472, USA.
⁴ Rice Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China.
⁵ Guangdong Key Laboratory of New Technology in Rice Breeding, Guangzhou, 510640, China.
⁶ Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA. rgregory@enders.tch.harvard.edu.
⁷ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. rgregory@enders.tch.harvard.edu.
⁸ Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. rgregory@enders.tch.harvard.edu.
⁹ Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. rgregory@enders.tch.harvard.edu.
¹⁰ Harvard Initiative for RNA Medicine, Boston, MA, 02115, USA. rgregory@enders.tch.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cell Nucleus* / metabolism
Exons / genetics
RNA Splicing* / genetics
RNA Stability / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding