Exon junction complex shapes the m(6)A epitranscriptome

N6-methyladenosine (m(6)A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m(6)A 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 re...

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Autores principales: Yang, Xin, Triboulet, Robinson, Liu, Qi, Sendinc, Erdem, Gregory, Richard I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780246/
https://www.ncbi.nlm.nih.gov/pubmed/36550132
http://dx.doi.org/10.1038/s41467-022-35643-1
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author Yang, Xin
Triboulet, Robinson
Liu, Qi
Sendinc, Erdem
Gregory, Richard I.
author_facet Yang, Xin
Triboulet, Robinson
Liu, Qi
Sendinc, Erdem
Gregory, Richard I.
author_sort Yang, Xin
collection PubMed
description N6-methyladenosine (m(6)A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m(6)A 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 m(6)A distribution remains enigmatic. Here we find the exon junction complex shapes the m(6)A landscape by blocking METTL3-mediated m(6)A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m(6)A 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 m(6)A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m(6)A mRNA modification are established and uncover a role of the EJC in shaping the m(6)A epitranscriptome.
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spelling pubmed-97802462022-12-24 Exon junction complex shapes the m(6)A epitranscriptome Yang, Xin Triboulet, Robinson Liu, Qi Sendinc, Erdem Gregory, Richard I. Nat Commun Article N6-methyladenosine (m(6)A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m(6)A 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 m(6)A distribution remains enigmatic. Here we find the exon junction complex shapes the m(6)A landscape by blocking METTL3-mediated m(6)A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m(6)A 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 m(6)A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m(6)A mRNA modification are established and uncover a role of the EJC in shaping the m(6)A epitranscriptome. Nature Publishing Group UK 2022-12-23 /pmc/articles/PMC9780246/ /pubmed/36550132 http://dx.doi.org/10.1038/s41467-022-35643-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yang, Xin
Triboulet, Robinson
Liu, Qi
Sendinc, Erdem
Gregory, Richard I.
Exon junction complex shapes the m(6)A epitranscriptome
title Exon junction complex shapes the m(6)A epitranscriptome
title_full Exon junction complex shapes the m(6)A epitranscriptome
title_fullStr Exon junction complex shapes the m(6)A epitranscriptome
title_full_unstemmed Exon junction complex shapes the m(6)A epitranscriptome
title_short Exon junction complex shapes the m(6)A epitranscriptome
title_sort exon junction complex shapes the m(6)a epitranscriptome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780246/
https://www.ncbi.nlm.nih.gov/pubmed/36550132
http://dx.doi.org/10.1038/s41467-022-35643-1
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AT sendincerdem exonjunctioncomplexshapesthem6aepitranscriptome
AT gregoryrichardi exonjunctioncomplexshapesthem6aepitranscriptome

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