State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
EMBO J. 2015 Feb 3;34(3):361-78. doi: 10.15252/embj.201489957. Epub 2014 Dec 17.
MicroRNAs play important roles in controlling the embryonic stem cell (ESC) state. Although much is known about microRNAs maintaining ESC state, microRNAs that are responsible for promoting ESC differentiation are less reported. Here, by screening 40 microRNAs pre-selected by their expression patterns and predicted targets in Dgcr8-null ESCs, we identify 14 novel differentiation-associated microRNAs. Among them, miR-27a and miR-24, restrained by c-Myc in ESC, exert their roles of silencing self-renewal through directly targeting several important pluripotency-associated factors, such as Oct4, Foxo1 and Smads. CRISPR/Cas9-mediated knockout of all miR-27/24 in ESCs leads to serious deficiency in ESC differentiation in vitro and in vivo. Moreover, depleting of them in mouse embryonic fibroblasts can evidently promote somatic cell reprogramming. Altogether, our findings uncover the essential role of miR-27 and miR-24 in ESC differentiation and also demonstrate novel microRNAs responsible for ESC differentiation.
微小 RNA 在调控胚胎干细胞 (ESC) 状态中发挥重要作用。尽管人们对维持 ESC 状态的微小 RNA 有了很多了解，但负责促进 ESC 分化的微小 RNA 报道较少。在这里，我们通过筛选 40 种预先根据其表达模式和 Dgcr8 缺失 ESC 中的预测靶点选择的微小 RNA，鉴定出 14 种新的分化相关微小 RNA。其中，miR-27a 和 miR-24 在 ESC 中受 c-Myc 抑制，通过直接靶向几个重要的多能性相关因子，如 Oct4、Foxo1 和 Smads，发挥沉默自我更新的作用。CRISPR/Cas9 介导的 ESCs 中所有 miR-27/24 的敲除导致体外和体内 ESC 分化严重不足。此外，在小鼠胚胎成纤维细胞中耗尽它们可以明显促进体细胞重编程。总之，我们的研究结果揭示了 miR-27 和 miR-24 在 ESC 分化中的重要作用，也证明了新的微小 RNA 负责 ESC 分化。
