Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis
Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis
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DOI：
10.1038/nature03817
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发表时间：
2005-07-14
期刊：
影响因子：
64.8
通讯作者：
Srivastava, D
中科院分区：
文献类型：
--
作者：
Zhao, Y;Samal, E;Srivastava, D
信号和转录因子的梯度控制着胚胎发生的许多方面，突出了调节蛋白水平的时空控制的必要性。 MicroRNA 是系统发育上保守的小 RNA，可调节目标信使 RNA 的翻译，提供蛋白质剂量调节的机制。在这里，我们发现 microRNA-1-1 (miR-1-1) 和 miR-1-2 在心肌和骨骼肌前体细胞中特异性表达。我们发现 miR-1 基因是肌肉分化调节因子（包括血清反应因子、MyoD 和 Mef2）的直接转录靶标。相应地，发育中的心脏中过量的 miR-1 会导致增殖的心室心肌细胞池减少。使用一种新的 microRNA 靶标识别算法，该算法结合了 RNA 结构和靶标可及性的特征，我们发现 Hand2（一种促进心室心肌细胞扩张的转录因子）是 miR-1 的靶标。这项工作表明，miR-1 基因滴定关键心脏调节蛋白的作用，以控制心脏发生过程中分化和增殖之间的平衡。
Gradients of signalling and transcription factors govern many aspects of embryogenesis, highlighting the need for spatiotemporal control of regulatory protein levels. MicroRNAs are phylogenetically conserved small RNAs that regulate the translation of target messenger RNAs, providing a mechanism for protein dose regulation. Here we show that microRNA-1-1 (miR-1-1) and miR-1-2 are specifically expressed in cardiac and skeletal muscle precursor cells. We found that the miR-1 genes are direct transcriptional targets of muscle differentiation regulators including serum response factor, MyoD and Mef2. Correspondingly, excess miR-1 in the developing heart leads to a decreased pool of proliferating ventricular cardiomyocytes. Using a new algorithm for microRNA target identification that incorporates features of RNA structure and target accessibility, we show that Hand2, a transcription factor that promotes ventricular cardiomyocyte expansion, is a target of miR-1. This work suggests that miR-1 genes titrate the effects of critical cardiac regulatory proteins to control the balance between differentiation and proliferation during cardiogenesis.