MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells
MiR-184 directly targets Wnt3 in cardiac mesoderm differentiation of embryonic stem cells
复制标题
MiR-184直接靶向胚胎干细胞心脏中胚层分化中的Wnt3
DOI：
10.1002/stem.3282
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发表时间：
2020-10-09
期刊：
影响因子：
5.2
通讯作者：
Wang, Guiying
中科院分区：
文献类型：
--
作者：
Liu, Xiaoqin;Yang, Yiwei;Wang, Guiying
胚胎干细胞具有自我更新和多向分化的特性，为研究早期胚胎体外发育提供了理想的模型。Wnt 3作为Wnt家族成员3，在ES细胞分化过程中起着重要作用。然而，Wnt 3的确切调控机制仍有待阐明。microRNA在转录后水平直接调控基因表达，在细胞命运决定中起着重要作用。我们发现miR-184在ES细胞向心肌中胚层分化时表达水平降低，在向心肌细胞分化过程中表达水平升高，与Wnt 3的表达呈负相关。在ES细胞向心脏中胚层分化的过程中，miR-184的过表达抑制了心脏中胚层的分化和心肌细胞的形成。生物信息学预测和机制研究表明，miR-184直接与Wnt 3的3 ' UTR区域结合，抑制Wnt 3的表达水平。因此，Wnt 3的敲低模拟了miR-184过表达对ES细胞向心脏中胚层分化的影响，而Wnt 3的过表达则挽救了miR-184过表达对ES细胞分化的抑制作用。这些结果表明，miR-184是ES细胞分化过程中Wnt 3的直接调控因子，进一步丰富了ES细胞向心脏中胚层和心肌细胞分化的表观遗传调控网络。
Embryonic stem (ES) cells have the property of self-renewal and multi-directional differentiation, and provide an ideal model for studying early embryo development in vitro. Wnt3, as Wnt family member 3, plays a vital role during ES cell differentiation. However, the exact regulatory mechanism of Wnt3 remains to be elucidated. MicroRNAs can directly regulate gene expression at the post-transcriptional level and play critical function in cell fate determination. Here, we found the expression level of miR-184 decreased when ES cells differentiated into cardiac mesoderm then increased during the process as differentiated into cardiomyocytes, which negatively correlated with the expression ofWnt3. Overexpression of miR-184 during the process of ES cell differentiation into cardiac mesoderm repressed cardiac mesoderm differentiation and cardiomyocyte formation. Bioinformatics prediction and mechanism studies showed that miR-184 directly bound to the 3 ' UTR region ofWnt3and inhibited the expression level ofWnt3. Consistently, knockdown ofWnt3mimicked the effects of miR-184-overexpression on ES cell differentiation into cardiac mesoderm, whereas overexpression ofWnt3rescued the inhibition effects of miR-184 overexpression on ES cell differentiation. These findings demonstrated that miR-184 is a direct regulator ofWnt3during the differentiation process of ES cells, further enriched the epigenetic regulatory network of ES cell differentiation into cardiac mesoderm and cardiomyocytes.