Exon junction complex shapes the m6A epitranscriptome

被引：82
作者：
Yang, Xin [1 ,2 ]
Triboulet, Robinson [1 ,2 ,6 ]
Liu, Qi [1 ,2 ,7 ,8 ]
Sendinc, Erdem [1 ,2 ]
Gregory, Richard I. [1 ,2 ,3 ,4 ,5 ]
机构：
[1] Boston Childrens Hosp, Div Hematol Oncol, Stem Cell Program, Boston, MA 02115 USA
[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[3] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA
[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[5] Harvard Initiat RNA Med, Boston, MA 02115 USA
[6] Twentyeight Seven Therapeut, Watertown, MA 02472 USA
[7] Guangdong Acad Agr Sci, Rice Res Inst, Guangzhou 510640, Peoples R China
[8] Guangdong Key Lab New Technol Rice Breeding, Guangzhou 510640, Peoples R China
来源：
NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期
关键词：
MESSENGER-RNA METHYLATION; NUCLEAR-RNA; TRANSLATION; REVEALS; BINDING; METTL3; STEM; N6-METHYLADENOSINE; DEMETHYLATION; BIOGENESIS;
D O I：
10.1038/s41467-022-35643-1
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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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页数：12
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