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

Jia, Wen and Deshmukh, Abhijeet and Mani, Sendurai A and Jolly, Mohit Kumar and Levine, Herbert (2019) A possible role for epigenetic feedback regulation in the dynamics of the epithelial-mesenchymal transition (EMT). In: PHYSICAL BIOLOGY, 16 (6).

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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 EMT-inducing signal for a sufficiently long period of time and then allowed to recover. Our preliminary experimental data indicates that a chronic TGF-beta 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.

Item Type:	Journal Article
Publication:	PHYSICAL BIOLOGY
Publisher:	IOP PUBLISHING LTD
Additional Information:	copyright for this article belongs to IOP PUBLISHING LTD
Keywords:	epithelial-mesenchymal transition; mathematical modeling; epigenetic regulation
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited:	04 Nov 2019 09:10
Last Modified:	04 Nov 2019 09:10
URI:	http://eprints.iisc.ac.in/id/eprint/63668

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