An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and Mesenchymal States.
An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and Mesenchymal States.
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DOI：
10.1371/journal.pcbi.1004569
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发表时间：
2015-11
影响因子：
4.3
通讯作者：
Dai X
中科院分区：
文献类型：
--
作者：
Hong T;Watanabe K;Ta CH;Villarreal-Ponce A;Nie Q;Dai X
可逆的上皮-间质转化（EMT）是组织发育、上皮干细胞和癌症转移的核心。虽然许多调控元件已被确定为诱导EMT，这种细胞可塑性的复杂过程仍然知之甚少。利用系统生物学方法集成建模和实验，我们发现多个中间状态有助于EMT和转换的鲁棒性是由转录因子Ovol 2调制。特别是，我们获得了Ovol 2和EMT诱导剂Zeb 1之间相互抑制关系的证据，并观察到，添加这种调节产生了一种新的四态系统，由两种不同的中间表型组成，它们在分化倾向上不同，在不同的环境条件下受到青睐。我们鉴定了天然存在于具有双向分化潜能的中间状态的上皮细胞，并发现EMT促进和抑制因子之间的平衡在实现和选择中间状态中至关重要。我们的分析表明，通过多个中间细胞命运控制细胞可塑性的一个新的设计原则，并强调了Ovol 2及其相关的分子调控的关键参与。累积的证据显示体细胞具有显著的谱系可塑性。上皮细胞向间充质细胞转化（EMT）代表了这种可塑性的一个主要例子，其中上皮细胞转化为间充质细胞。这一过程在正常发育中用于产生关键的细胞类型，并被癌细胞劫持以进行侵袭和转移。最近的研究也表明EMT在产生干细胞特性中的重要性。EMT的可逆性及其对不同环境刺激的敏感性对理解指导细胞状态转换及其动态的复杂调控网络提出了有趣的挑战。在这里，我们使用系统生物学的方法来探讨EMT过程的复杂性。我们报告了一种新的分子调控，扩展了已知的调控网络，并表明这种新的网络能够产生多个中间状态，我们提供了实验证据。我们目前的建模和实验结果，突出EMT促进和抑制因素之间的微妙平衡的意义，实现和/或选择一个中间状态，并建议多个中间状态的生物学意义。这项工作进一步阐明了控制上皮细胞行为和癌症/干细胞可塑性的复杂策略。
Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach integrating modeling and experiments, we found multiple intermediate states contributing to EMT and that the robustness of the transitions is modulated by transcriptional factor Ovol2. In particular, we obtained evidence for a mutual inhibition relationship between Ovol2 and EMT inducer Zeb1, and observed that adding this regulation generates a novel four-state system consisting of two distinct intermediate phenotypes that differ in differentiation propensities and are favored in different environmental conditions. We identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to be critical in achieving and selecting between intermediate states. Our analysis suggests a new design principle in controlling cellular plasticity through multiple intermediate cell fates and underscores the critical involvement of Ovol2 and its associated molecular regulations. Cumulative evidence reveals remarkable lineage plasticity of somatic cells. Epithelial-to-mesenchymal transition (EMT) represents a prime example of such plasticity where an epithelial cell is converted into a mesenchymal cell. This process is used in normal development to generate crucial cell types, and is hijacked by cancer cells for invasion and metastasis. Recent studies also suggest the importance of EMT in generating stem cell properties. The reversibility of EMT and its sensitivity to varying environmental stimuli pose interesting challenges to understand the intricate regulatory networks that direct cellular state transitions and their dynamics. Here we use a systems biology approach to probe into the complexity of the EMT process. We report a new molecular regulation that expands the known regulatory network, and show that this new network is capable of generating multiple intermediate states, which we provide experimental evidence for. We present modeling and experimental results to highlight the significance of a delicate balance between EMT-promoting and -inhibiting factors for achieving and/or selecting an intermediate state, and to suggest the biological significance of the multiple intermediate states. This work further elucidates the complex strategies that control epithelial cell behavior and cancer/stem cell plasticity.