A possible role for epigenetic feedback regulation in the dynamics of the Epithelial-Mesenchymal Transition (EMT)

Abstract

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 EMTinducing signal for a sufficiently long period of time and then allowed to recover. Our preliminary experimental data indeed shows that a prolonged TGF-β exposure gives rise to increasing difficult reversion back to the epithelial state. Thus, this integrated theoretical-

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

“…The degree of reversibility of EMT has been proposed to be largely a function of the timescale of EMT induction and corresponding epigenetic changes. However, a causative role of epigenetic changes in regulating the irreversibility of EMT remains to be firmly established [11][12][13][14]. Here, we propose two independent mechanisms that may enable an irreversible MET: 1) epigenetic feedback mediated by the inhibitory action of GRHL2 on the promoter of ZEB1; and 2) noise in the partitioning of biomolecules during cell division.…”

“…Cells induced to undergo EMT for shorter durations (~2-6 days) may revert to an epithelial state after withdrawal of the signal/stimulus. However, some cells exposed to EMT-inducing signals for longer durations (~10 days or more) may get "locked" in a mesenchymal state, making EMT largely irreversible, at least for the timescale observed experimentally [11][12][13][14]. The possibility of an irreversible EMT is also supported by multiple phenomenological observations [15][16][17].…”

“…Multiple mechanisms have been proposed to explain the existence of a "tipping point"-a time point beyond which continued treatment with EMT inducing signals can drive an irreversible EMT. These include self-stabilizing feedback loops [18][19][20][21] in the regulatory circuits for EMT/ MET and/or epigenetic alterations [13,22,23]. However, similar investigations about the irreversibility of MET, or in other words, the resistance of epithelial cells to undergo EMT in response to EMT-inducing signals, remain to be done.…”

“…GRHL2 and miR-200 both form mutually inhibitory feedback loops with ZEB1-a key EMT-inducing transcription factor (EMT-TF) [31]. Previously, we have shown that incorporating an epigenetic feedback term acting on the inhibition of miR-200 by ZEB1 could drive an irreversible EMT [13]. This epigenetic feedback term was incorporated at a phenomenological level to represent the idea that the longer a gene is turned on, the easier it becomes for it to stay transcriptionally active; thus, epigenetic feedback can modulate the thresholds for the influence of a transcription factor on its downstream target [32,33].…”

Gene expression profiles of inflammatory breast cancer reveal high heterogeneity across the epithelial-hybrid-mesenchymal spectrum

“…Extensive efforts have been undertaken to identify unique gene expression signatures of IBC. In 2013, the IBC World Consortium identified a 79-gene signature that focused on the inhibition of TGFβ signaling as molecular footprint of IBC [6]; this was consistent with experimental observations that weakened TGFβ signaling promoted collective cell invasion, a hallmark of IBC, while a strong activation of TGFβ signaling promotes individual invasion consistent with a full-blown EMT [7][8][9]. However, later, these differences were found to arise due to difference in incidence of HER2-positive subtype in IBC vs. non-IBC samples used [1].…”