From the Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
J Biol Chem. 2013 Sep 13;288(37):26865-77. doi: 10.1074/jbc.M112.440453. Epub 2013 Jul 19.
MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that function as negative regulators of gene expression. They are transcribed from endogenous DNA and form hairpin structures (termed as pre-miRNAs) that are processed to form mature miRNAs. It remains largely unknown as to the molecular consequences of the natural genetic variation in pre-miRNAs. Here, we report that an A→G polymorphism (rs71428439) is located in Homo sapiens miR-149 stem-loop region. This polymorphism results in a change in the structure of the miR-149 precursor. Our results showed that the genotype distribution of this polymorphism in myocardial infarction cases was significantly different from that in the control subjects. We examined the biological significance of this polymorphism on the production of mature miR-149, and we observed that the G-allelic miR-149 precursor displayed a lower production of mature miR-149 compared with the A-allelic one. Further investigations disclosed that miR-149 could withstand mitochondrial fission and apoptosis through targeting the pro-apoptotic factor p53-up-regulated modulator of apoptosis (Puma). Enforced expression of miR-149 promoted cell survival, whereas knockdown of miR-149 rendered cells to be sensitive to apoptotic stimulation. Intriguingly, the A to G variation led pre-miR-149 to elicit an attenuated effect on the inhibition of mitochondrial fission and apoptosis. Finally, this polymorphism exerts its influence on cardiac function in the mouse model of myocardial infarction. These data suggest that this polymorphism in the miR-149 precursor may result in important phenotypic traits of myocardial infarction. Our findings warrant further investigations on the relationship between miR-149 polymorphism and myocardial infarction.
微小 RNA（miRNAs）是小的、单链、非编码 RNA，作为基因表达的负调控因子发挥作用。它们由内源性 DNA 转录而来，并形成发夹结构（称为前 miRNA），这些发夹结构被加工形成成熟的 miRNA。目前，关于前 miRNA 中自然遗传变异的分子后果在很大程度上仍不清楚。在这里，我们报告一个 A→G 多态性（rs71428439）位于人类 miR-149 茎环区域。这种多态性导致 miR-149 前体结构发生变化。我们的结果表明，该多态性在心肌梗死病例中的基因型分布与对照组明显不同。我们研究了这种多态性对成熟 miR-149 产生的生物学意义，观察到 G 等位基因的 miR-149 前体产生的成熟 miR-149 明显低于 A 等位基因。进一步的研究表明，miR-149 可以通过靶向促凋亡因子 p53 上调凋亡调节剂（Puma）来抵抗线粒体裂变和凋亡。强制表达 miR-149 促进细胞存活，而敲低 miR-149 则使细胞对凋亡刺激敏感。有趣的是，A 到 G 的变异导致前 miR-149 对抑制线粒体裂变和凋亡的作用减弱。最后，这种多态性对心肌梗死小鼠模型的心脏功能产生影响。这些数据表明，miR-149 前体中的这种多态性可能导致心肌梗死的重要表型特征。我们的发现需要进一步研究 miR-149 多态性与心肌梗死之间的关系。
