miR-34 miRNAs provide a barrier for somatic cell reprogramming.
miR-34 miRNAs provide a barrier for somatic cell reprogramming.
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DOI：
10.1038/ncb2366
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发表时间：
2011-10-23
影响因子：
21.3
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由定义的转录因子诱导的体细胞重编程是一个低效率的过程，p53缺乏会增强这一过程。迄今为止，p21是唯一一个p53靶点，可以抑制iPSC（诱导多能干细胞）的生成，这表明其他p53靶点可能调节这一过程。在这里，我们证明了mir-34 microrna (mirna)，特别是miR-34a，在重编程过程中表现出p53依赖性诱导。小鼠mir-34a缺失显著增加重编程效率和动力学，mir-34a和p21协同调节p53下游的体细胞重编程。与p53缺陷不同，p53缺陷以牺牲iPSC多能性为代价增强重编程，mir-34a的基因消融促进iPSC的生成，而不影响自我更新和分化。miR-34a对重编程的抑制，至少部分是由于多能基因的抑制，包括Nanog、Sox2和Mycn （N-Myc）。miR-34a的转录后基因抑制也调节了iPSC分化动力学。miR-34b和c同样抑制重编程；三种mir-34 mirna在此过程中协同作用。综上所述，我们的研究结果确定了mir-34 mirna作为p53的新靶点，在抑制体细胞重编程中发挥重要作用。
Somatic reprogramming induced by defined transcription factors is a low efficiency process that is enhanced by p53 deficiency . To date, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation , suggesting additional p53 targets may regulate this process. Here, we demonstrated that mir-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. mir-34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation of mir-34a promoted iPSC generation without compromising self-renewal and differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three mir-34 miRNAs acted cooperatively in this process. Taken together, our findings identified mir-34 miRNAs as novel p53 targets that play an essential role in restraining somatic reprogramming.
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