Wnt/β-catenin信号通路中microRNA的表达调控及功能研究

Recent findings have shown that microRNAs (miRNAs), as important as proteins within signaling pathways, play key roles in cell function and fate decision. However, the process and mechanism of coordinated regulation between miRNAs and signaling pathway in cell remains to be elucidated. In the previous study we found the levels of numerous miRNAs to change following the activation of the Wnt/beta-catenin pathway. Among these miRNAs, we showed that TCF/LEF1, the core transcription factors of the Wnt/beta-catenin pathway directly transactivated the miR-371-373 cluster, which in turn, activated the Wnt/beta-catenin signaling through a positive feedback loop. On this basis, our project will develop new algorithms and analysis platforms based on integration of next-generation sequencing data and chromosomal open structure characteristics to systematically identify the transcription factor binding sites and the functional targetome of miRNAs. Using an integrative approach of experiments and bioinformatics, our project will demonstrate the expression and transcriptional regulation of miRNAs that are directly controlled by Wnt/beta-catenin signaling pathway upon different states (activation or inhibition), as well as the function of those TCF/LEF1-regulated miRNAs involved in stem cell maintenance and tumorigenesis. Altogether, the study will expand our understanding on the mechanism of coordinated regulation between miRNAs and the Wnt signaling pathway.

近年来发现，miRNA与细胞重要信号通路蛋白一样，在细胞功能和命运决定中起关键作用。但是，目前miRNA与重要信号通路之间的协同调控过程及机制还有待阐明。我们前期研究表明，Wnt/β-catenin信号通路激活后，一批miRNA表达发生显著变化，其中miR-371-373基因簇直接受信号通路核心转录因子TCF/LEF1调控并反馈激活Wnt/β-catenin通路。在此基础上，本项目拟结合实验和生物信息方法，并开发整合新一代测序数据和染色体开放结构特征等鉴定转录因子结合位点的新算法及miRNA功能靶标组分析平台，系统研究Wnt/β-catenin信号通路及不同状态（激活或抑制）下miRNA的变化及其表达调控的分子机制，解析信号通路核心转录因子TCF/LEF1直接转录调控的miRNA的功能及其在干细胞维持、肿瘤发生等生物学过程中的作用，拓展我们对miRNA与Wnt信号通路协同调控机制的认识。

本项目开发整合新一代测序数据和染色体开放结构特征等鉴定转录因子结合位点的新算法及miRNA 功能靶标组分析平台，建立了ChiPBase、starBase2.0 和deepBase2.0 等先进的RNA组学技术及信息库；通过体内体外实验模型，阐明miR-150和 miR-372/373等Wnt信号通路直接转录激活的miRNA在干细胞维持、肿瘤发生等生理和病理中的作用及机制。此外，研究发现和阐明了肌细胞分化相关微RNA（mamiRs）抑制JNK信号通路磷酸化来控制骨骼肌细胞分化的新机制；研究还揭示和阐明了天然药物冬凌草甲素对癌细胞关键信号通路的作用及调控机制。这些研究极大地拓展我们对miRNA 与信号通路协同调控机制的认识。

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