A Possible Role for Epigenetic Feedback Regulation in the Dynamics of the Epithelial-mesenchymal Transition (EMT)

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.