A possible role for epigenetic feedback regulation in the dynamics of the epithelial–mesenchymal transition (EMT)*

Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis and drug resistance, and involves epigenetic remodeling. However, how epigenetic changes affecting the dynamical traits such as plasticity or memory are not fully understood. Here, we analyzed the effects of epigenetic feedback on EMT through integrating this feedback on various aspects of the miR-200/ZEB loop – a core circuit regulating EMT. Epigenetic feedback on self-activation of ZEB has minor effects in population distribution and transition times, but epigenetic feedback on the inhibition of miR-200 by ZEB can largely stabilize the mesenchymal state, thus making the process irreversible. Follow-up preliminary experiments show that when EMT is induced in epithelial cells , a certain percentage of cells can stay in mesenchymal state after the inducing signal is removed. This percentage depends on the extent of induction of EMT, thus well recapitulating our model-based predictions.