Exon architecture controls mRNA m6A suppression and gene expression

P Cody He; Jiangbo Wei; Xiaoyang Dou; Bryan T Harada; Zijie Zhang; Ruiqi Ge; Chang Liu; Li-Sheng Zhang; Xianbin Yu; Shuai Wang; Ruitu Lyu; Zhongyu Zou; Mengjie Chen; Chuan He

doi:10.1126/science.abj9090

Exon architecture controls mRNA m⁶A suppression and gene expression

Science. 2023 Feb 17;379(6633):677-682. doi: 10.1126/science.abj9090. Epub 2023 Jan 27.

Authors

P Cody He^#^{1

2

3}, Jiangbo Wei^#^{1

3}, Xiaoyang Dou^#^{1

3}, Bryan T Harada^#^{1

3}, Zijie Zhang^{1

3

4}, Ruiqi Ge^{1

3}, Chang Liu^{1

3}, Li-Sheng Zhang^{1

3}, Xianbin Yu^{1

3}, Shuai Wang⁵, Ruitu Lyu^{1

3}, Zhongyu Zou^{1

3}, Mengjie Chen^{6

7}, Chuan He^{1

2

3}

Affiliations

¹ Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
² Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
³ Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
⁴ State Key Laboratory for Conservation and Utilization of Bio-Resources, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China.
⁵ Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
⁶ Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
⁷ Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.

^# Contributed equally.

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant messenger RNA (mRNA) modification and plays crucial roles in diverse physiological processes. Using a massively parallel assay for m⁶A (MPm⁶A), we discover that m⁶A specificity is globally regulated by suppressors that prevent m⁶A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m⁶A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m⁶A suppression. EJC suppression of m⁶A underlies multiple global characteristics of mRNA m⁶A specificity, with the local range of EJC protection sufficient to suppress m⁶A deposition in average-length internal exons but not in long internal and terminal exons. EJC-suppressed methylation sites colocalize with EJC-suppressed splice sites, which suggests that exon architecture broadly determines local mRNA accessibility to regulatory complexes.

MeSH terms

Animals
Exons*
Gene Expression Regulation*
Humans
RNA Splicing*
RNA, Messenger* / genetics
RNA, Messenger* / metabolism

Substances

RNA, Messenger
N-methyladenosine

Abstract

MeSH terms

Substances

Grants and funding