Department of Medicine, Duke University Medical Center, Durham, NC, 27705, USA.
The RNA Institute, State University of New York, Albany, NY, 12222, USA.
Nat Commun. 2019 Jul 30;10(1):3401. doi: 10.1038/s41467-019-11375-7.
Epitranscriptomic modifications of mRNA are important regulators of gene expression. While internal 2'-O-methylation (Nm) has been discovered on mRNA, questions remain about its origin and function in cells and organisms. Here, we show that internal Nm modification can be guided by small nucleolar RNAs (snoRNAs), and that these Nm sites can regulate mRNA and protein expression. Specifically, two box C/D snoRNAs (SNORDs) and the 2'-O-methyltransferase fibrillarin lead to Nm modification in the protein-coding region of peroxidasin (Pxdn). The presence of Nm modification increases Pxdn mRNA expression but inhibits its translation, regulating PXDN protein expression and enzyme activity both in vitro and in vivo. Our findings support a model in which snoRNA-guided Nm modifications of mRNA can regulate physiologic gene expression by altering mRNA levels and tuning protein translation.
mRNA 的转录后修饰是基因表达的重要调节因子。虽然在 mRNA 上已经发现了内部 2'-O-甲基化 (Nm)，但其在细胞和生物体中的起源和功能仍存在疑问。在这里，我们表明内部 Nm 修饰可以由小核仁 RNA (snoRNA) 指导，并且这些 Nm 位点可以调节 mRNA 和蛋白质的表达。具体来说，两种框 C/D snoRNA (SNORD) 和 2'-O-甲基转移酶 fibrillarin 导致过氧化物酶 (Pxdn) 蛋白编码区的 Nm 修饰。Nm 修饰的存在增加了 Pxdn mRNA 的表达，但抑制了其翻译，从而调节了 PXDN 蛋白的表达和酶活性，无论是在体外还是体内。我们的研究结果支持这样一种模型，即 snoRNA 指导的 mRNA Nm 修饰可以通过改变 mRNA 水平和调节蛋白质翻译来调节生理基因表达。
