The epithelial-mesenchymal transition (EMT) often plays a critical role in cancer metastasis and chemoresistance, and decoding its dynamics is crucial to design effective therapeutics. EMT is regulated at multiple levels-transcriptional, translational, protein stability and epigenetics; the mechanisms by which epigenetic regulation can alter the dynamics of EMT remain elusive. Here, to identify the possible effects of epigenetic regulation in EMT, we incorporate a feedback term in our previously proposed model of EMT regulation of the miR-200/ZEB/miR-34/SNAIL circuit. This epigenetic feedback that stabilizes long-term transcriptional activity can alter the relative stability and distribution of states in a given cell population, particularly when incorporated in the inhibitory effect on miR-200 from ZEB. This feedback can stabilize the mesenchymal state, thus making transitions out of that state difficult. Conversely, epigenetic regulation of the self-activation of ZEB has only minor effects. Our model predicts that this effect could be seen in experiments, when epithelial cells are treated with an external EMT-inducing signal for a sufficiently long period of time and then allowed to recover. Our preliminary experimental data indicates that a chronic TGF-β exposure gives rise to irreveversible EMT state; i.e. unable to reverse back to the epithelial state. Thus, this integrated theoretical-experimental approach yields insights into how an epigenetic feedback may alter the dynamics of EMT.

中文翻译：

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表观遗传反馈调节在上皮-间质转化（EMT）动力学中的可能作用。

上皮-间质转化（EMT）通常在癌症转移和化学耐药中起关键作用，而对其动态进行解码对于设计有效的治疗方法至关重要。EMT在转录，翻译，蛋白质稳定性和表观遗传学等多个层面受到调控；表观遗传调控可以改变EMT动态的机制仍然难以捉摸。在这里，为了确定表观遗传调控对EMT的可能影响，我们在先前提出的miR-200 / ZEB / miR-34 / SNAIL电路的EMT调控模型中加入了一个反馈项。稳定长期转录活性的这种表观遗传学反馈可以改变给定细胞群中状态的相对稳定性和状态分布，特别是当掺入ZEB对miR-200的抑制作用时。该反馈可以稳定间充质状态，从而使从该状态的转变变得困难。相反，ZEB自我激活的表观遗传调控只有很小的作用。我们的模型预测，当用外部EMT诱导信号处理上皮细胞足够长的时间，然后使其恢复时，可以在实验中看到这种效果。我们的初步实验数据表明，长期暴露于TGF-β会导致不可逆的EMT状态。即无法逆转回到上皮状态。因此，这种综合的理论-实验方法产生了关于表观遗传反馈如何改变EMT动态的见解。我们的模型预测，当用外部EMT诱导信号处理上皮细胞足够长的时间，然后使其恢复时，可以在实验中看到这种效果。我们的初步实验数据表明，长期暴露于TGF-β会导致不可逆的EMT状态。即无法逆转回到上皮状态。因此，这种综合的理论-实验方法产生了关于表观遗传反馈如何改变EMT动态的见解。我们的模型预测，当用外部EMT诱导信号处理上皮细胞足够长的时间，然后使其恢复时，可以在实验中看到这种效果。我们的初步实验数据表明，长期暴露于TGF-β会导致不可逆的EMT状态。即无法逆转回到上皮状态。因此，这种综合的理论-实验方法产生了关于表观遗传反馈如何改变EMT动态的见解。无法逆转回到上皮状态。因此，这种综合的理论-实验方法产生了关于表观遗传反馈如何改变EMT动态的见解。无法逆转回到上皮状态。因此，这种综合的理论-实验方法产生了关于表观遗传反馈如何改变EMT动态的见解。