Exon architecture controls mRNA m6A suppression and gene expression

• 成果类型: Article
• 署名作者: He, P. Cody; Wei, Jiangbo; Dou, Xiaoyang; Harada, Bryan T.; Zhang, Zijie; Ge, Ruiqi; Liu, Chang; Zhang, Li-Sheng; Yu, Xianbin; Wang, Shuai; Lyu, Ruitu; Zou, Zhongyu; Chen, Mengjie; He, Chuan
• 署名单位: University of Chicago; University of Chicago; University of Chicago; Howard Hughes Medical Institute; Yunnan University; University of Chicago; University of Chicago; University of Chicago; University of California System; University of California San Diego
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9484
• DOI: 10.1126/science.abj9090
• 发表日期: 2023-02-17
• 页码: 677-682
• 关键词: interactome reveals; n-6-methyladenosine

摘要

N-6-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 (MPm(6)A), we discover that m(6)A specificity is globally regulated by suppressors that prevent m6A deposition in unmethylated transcriptome regions. We identify exon junction complexes (EJCs) as m(6)A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m(6)A suppression. EJC suppression of m6A underlies multiple global characteristics of mRNA m(6)A 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.