Center for Theoretical Biological Physics and Departments of Bioengineering, Physics and Astronomy, Chemistry, and Biochemistry and Cell Biology, Rice University, Houston, TX 77005-1827.
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18144-9. doi: 10.1073/pnas.1318192110. Epub 2013 Oct 23.
Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules--the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. Here, we used detailed modeling of microRNA-based regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states--(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)--with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expression measurements in collectively migrating cells) and explains the lack of observed mesenchymal-to-hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented.
上皮细胞与间充质表型的向前和向后转变在胚胎发育和组织修复中起着关键作用。异常调节的转变也是癌症转移的一个标志。调节这些转变的遗传网络似乎允许存在混合表型(上皮/间充质)。杂交细胞具有混合的上皮和间充质特征,使其具有诸如集体细胞迁移等专门功能。三种表型之间的细胞命运决定实际上是由一个由两个高度相互连接的嵌合模块——miR-34/Snail 和 miR-200/ZEB 相互抑制反馈回路组成的电路来调节的。在这里,我们使用基于 microRNA 的调节的详细建模来研究这个核心单元。更具体地说,我们研究了两个分离模块的功能,然后研究了当两个模块整合到完整的调节回路中时,组合单元的功能。我们发现,miR-200/ZEB 形成一个三稳态电路,作为一个三元开关,由 miR-34/Snail 驱动,而 miR-34/Snail 是一个单稳态模块,作为内部和外部信号的噪声缓冲积分器。我们提出将三个稳定状态——(1,0)、(高 miR-200)/(低 ZEB);(0,1)、(低 miR-200)/(高 ZEB);和(1/2,1/2)、(中 miR-200)/(中 ZEB)——分别与上皮、间充质和混合表型相关联。我们的(1/2,1/2)状态假设与最近的实验研究一致(例如,在集体迁移细胞中测量 ZEB 表达),并解释了在转移性细胞和诱导多能干细胞中观察到的缺乏间充质到杂交转变的现象。提出了完整和部分转变期间动态基因表达的可测试预测。