Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
Department of Molecular Genetics and Cell Biology and the Center for Physics of Evolving Systems, University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2019 Jul 30;10(1):3414. doi: 10.1038/s41467-019-11232-7.
Despite the vast number of modification sites mapped within mRNAs, known examples of consequential mRNA modifications remain rare. Here, we provide multiple lines of evidence to show that Ime4p, an N6-methyladenosine (mA) methyltransferase required for meiosis in yeast, acts by methylating a site in the 3' UTR of the mRNA encoding Rme1p, a transcriptional repressor of meiosis. Consistent with this mechanism, genetic analyses reveal that IME4 functions upstream of RME1. Transcriptome-wide, RME1 is the primary message that displays both increased methylation and reduced expression in an Ime4p-dependent manner. In yeast strains for which IME4 is dispensable for meiosis, a natural polymorphism in the RME1 promoter reduces RME1 transcription, obviating the requirement for methylation. Mutation of a single mA site in the RME1 3' UTR increases Rme1p repressor production and reduces meiotic efficiency. These results reveal the molecular and physiological consequences of a modification in the 3' UTR of an mRNA.
尽管在 mRNA 中映射了大量的修饰位点，但已知的具有重要影响的 mRNA 修饰实例仍然很少。在这里，我们提供了多方面的证据表明，Ime4p，一种在酵母减数分裂中所必需的 N6-甲基腺苷（m6A）甲基转移酶，通过甲基化编码减数分裂转录抑制剂 Rme1p 的 mRNA 的 3'UTR 中的一个位点来发挥作用。与该机制一致，遗传分析表明 IME4 在 RME1 的上游起作用。在转录组范围内，RME1 是主要的 mRNA，它以依赖于 Ime4p 的方式显示出增加的甲基化和减少的表达。在 IME4 对于减数分裂并非必需的酵母菌株中，RME1 启动子中的一个自然多态性降低了 RME1 的转录，从而消除了对甲基化的需求。RME1 3'UTR 中单个 m6A 位点的突变会增加 Rme1p 抑制剂的产生并降低减数分裂效率。这些结果揭示了 mRNA 3'UTR 修饰的分子和生理后果。
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