Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming.
Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming.
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DOI：
10.1371/journal.pone.0132789
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ishii H
中科院分区：
文献类型：
--
作者：
Konno M;Koseki J;Kawamoto K;Nishida N;Matsui H;Dewi DL;Ozaki M;Noguchi Y;Mimori K;Gotoh N;Tanuma N;Shima H;Doki Y;Mori M;Ishii H
非编码microRNA抑制翻译并降低编码mRNA的转录稳定性，然而，在异常沉默基因组区域中的miR-369在细胞应激下稳定靶蛋白。我们发现，胚胎干细胞的体外分化导致小鼠染色体12 qF上miR-369区域的组蛋白H3 K4的染色质甲基化，该区域在胚胎细胞中表达，对多能性至关重要。蛋白质组学分析显示，miR-369稳定了丙酮酸激酶（Pkm 2）剪接因子（如HNRNPA 2B 1）的翻译。miR-369的过表达刺激Pkm 2剪接并增强诱导多能干细胞因子对细胞重编程的诱导，而miR-369的敲低导致抑制。此外，免疫沉淀分析显示Argonaute复合物以miR-369依赖的方式含有脆性X智力低下相关蛋白1和HNRNPA 2B 1。我们的研究结果证明了胚胎miR-369-HNRNPA 2B 1轴在控制代谢酶功能方面的独特作用，并提出了一种连接细胞重编程中表观遗传、转录和代谢控制的新途径。
Noncoding microRNAs inhibit translation and lower the transcript stability of coding mRNA, however miR-369 s, in aberrant silencing genomic regions, stabilizes target proteins under cellular stress. We found that in vitro differentiation of embryonic stem cells led to chromatin methylation of histone H3K4 at the miR-369 region on chromosome 12qF in mice, which is expressed in embryonic cells and is critical for pluripotency. Proteomic analyses revealed that miR-369 stabilized translation of pyruvate kinase (Pkm2) splicing factors such as HNRNPA2B1. Overexpression of miR-369 stimulated Pkm2 splicing and enhanced induction of cellular reprogramming by induced pluripotent stem cell factors, whereas miR-369 knockdown resulted in suppression. Furthermore, immunoprecipitation analysis showed that the Argonaute complex contained the fragile X mental retardation-related protein 1 and HNRNPA2B1 in a miR-369-depedent manner. Our findings demonstrate a unique role of the embryonic miR-369-HNRNPA2B1 axis in controlling metabolic enzyme function, and suggest a novel pathway linking epigenetic, transcriptional, and metabolic control in cell reprogramming.