美国芝加哥大学Chuan He团队近期取得重要工作进展，他们研究发现外显子结构调控mRNA的m⁶A修饰抑制和基因表达。相关研究成果2023年1月26日在线发表于《科学》杂志上。

据介绍，N⁶-甲基腺苷（m⁶A）是最丰富的mRNA修饰，在多种生理过程中发挥着关键作用。

利用m⁶A的大规模平行测定（MPm⁶A），研究人员发现m⁶A的特异性受到“抑制剂”的全面调节，这些抑制剂阻止m⁶A在非甲基化转录组区域沉积。研究人员将外显子连接复合物（EJC）鉴定为m⁶A抑制剂，可以保护编码序列内的外显子结合近端RNA免受甲基化，并通过m⁶A抑制调节mRNA的稳定性。EJC对m⁶A的抑制是mRNA m⁶A特异性的多种全局特征的基础，EJC的局部保护范围足以抑制平均长度的内部外显子中m⁶A的沉积，但在较长的内部和末端外显子上则不起作用。

总之，EJC抑制的甲基化位点与EJC抑制的剪接位点共同定位，表明外显子结构广泛决定了局部mRNA对调控复合物的可及性。

附：英文原文

Title: Exon architecture controls mRNA m6A suppression and gene expression

Author: 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

Issue&Volume: 2023-01-26

Abstract: N6–methyladenosine (m6A) is the most abundant mRNA modification and plays crucial roles in diverse physiological processes. Utilizing 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 co-localize with EJC-suppressed splice sites, suggesting that exon architecture broadly determines local mRNA accessibility to regulatory complexes.

DOI: abj9090

Source: https://www.science.org/doi/10.1126/science.abj9090