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Coupled Reversible and Irreversible Bistable Switches Underlying TGF beta-induced Epithelial to Mesenchymal Transition

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dc.contributorVirginia Techen
dc.contributor.authorTian, X. J.en
dc.contributor.authorZhang, H.en
dc.contributor.authorXing, Jianhuaen
dc.contributor.departmentBiological Sciencesen
dc.date.accessed2014-02-05en
dc.date.accessioned2014-02-26T19:10:02Zen
dc.date.available2014-02-26T19:10:02Zen
dc.date.issued2013-08en
dc.description.abstractEpithelial to mesenchymal transition (EMT) plays an important role in embryonic development, tissue regeneration, and cancer metastasis. Whereas several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-beta treatment. We construct a mathematical model for the core regulatory network controlling TGF-beta-induced EMT. Through deterministic analyses and stochastic simulations, we show that EMT is a sequential two-step program in which an epithelial cell first is converted to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-beta stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double-negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, whereas the ZEB/nniR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-beta/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Such coupled bistable switches are robust to parameter variation and molecular noise. We provide a mechanistic explanation on multiple experimental observations. The model makes several explicit predictions on hysteretic dynamic behaviors, system response to pulsed stimulation, and various perturbations, which can be straightforwardly tested.en
dc.description.sponsorshipNational Science Foundation DMS-0969417, DGE-0966125en
dc.identifier.citationTian, Xiao-Jun; Zhang, Hang; Xing, Jianhua, "Coupled Reversible and Irreversible Bistable Switches Underlying TGF beta-induced Epithelial to Mesenchymal Transition," Biophysical Journal 105(4), 1079-1089 (2013); doi: 10.1016/j.bpj.2013.07.011en
dc.identifier.doihttps://doi.org/10.1016/j.bpj.2013.07.011en
dc.identifier.issn0006-3495en
dc.identifier.urihttp://hdl.handle.net/10919/25758en
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0006349513007947en
dc.language.isoen_USen
dc.publisherCELL PRESSen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectdouble-negative feedbacken
dc.subjecttranscription factor snailen
dc.subjectmammalian-cellsen
dc.subjectgene-expressionen
dc.subjectcanceren
dc.subjectemten
dc.subjectprogressionen
dc.subjectmicrornasen
dc.subjectcadherinen
dc.subjectnetworken
dc.titleCoupled Reversible and Irreversible Bistable Switches Underlying TGF beta-induced Epithelial to Mesenchymal Transitionen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden

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