microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming
microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming
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microRNA-29b 是 Sox2 功能调节体细胞重编程的新型介质
DOI：
10.1038/cr.2012.180
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发表时间：
2013-01-01
期刊：
影响因子：
44.1
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
--
作者：
Guo, Xudong;Liu, Qidong;Kang, Jiuhong
成纤维细胞可以通过应用Yamanaka因子（OSKM）重编程为诱导多能干细胞（iPSC），但这种重编程的机制仍然知之甚少。在这里，我们报告说，Sox 2直接调节内源性microRNA-29 b（miR-29 b）的表达在iPSC的产生和miR-29 b的表达所需的OSKM和OSK介导的重编程。机制研究表明，Dnmt 3a和Dnmt 3b是miR-29 b的体内靶点，并且在重编程期间，Dnmt 3a和Dnmt 3b表达与miR-29 b表达呈负相关。此外，miR-29 b对重编程的影响可以通过Dnmt 3a或Dnmt 3b过表达来阻断。进一步的实验表明，miR-29 b-DNMT信号传导显著参与DNA甲基化相关的重编程事件的调节，例如间充质-上皮转化（MET）和Dlk 1-Dio 3区域转录。因此，我们的研究不仅揭示了miR-29 b是重编程因子Sox 2的新介质，而且还为Sox 2驱动miR-29 b-DNMT信号轴调节重编程过程中DNA甲基化相关事件的多步机制提供了证据。
Fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) by the application of Yamanaka factors (OSKM), but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b (miR-29b) expression during iPSC generation and that miR-29b expression is required for OSKM-and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition (MET) and Dlk1-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT signaling axis that regulates DNA methylation-related events during reprogramming.