Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition

Xiaojun Tian, Hang Zhang, Jianhua Xing

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Epithelial 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-β treatment. We construct a mathematical model for the core regulatory network controlling TGF-β-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-β 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/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/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.

Original languageEnglish (US)
Pages (from-to)1079-1089
Number of pages11
JournalBiophysical Journal
Volume105
Issue number4
DOIs
StatePublished - Aug 20 2013
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Embryonic Development
Noise
Regeneration
Theoretical Models
Epithelial Cells
Maintenance
Neoplasm Metastasis

ASJC Scopus subject areas

  • Biophysics

Cite this

Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition. / Tian, Xiaojun; Zhang, Hang; Xing, Jianhua.

In: Biophysical Journal, Vol. 105, No. 4, 20.08.2013, p. 1079-1089.

Research output: Contribution to journalArticle

@article{aa90e0e0a6cb446cbf1b436e0630d8e5,
title = "Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition",
abstract = "Epithelial 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-β treatment. We construct a mathematical model for the core regulatory network controlling TGF-β-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-β 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/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/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.",
author = "Xiaojun Tian and Hang Zhang and Jianhua Xing",
year = "2013",
month = "8",
day = "20",
doi = "10.1016/j.bpj.2013.07.011",
language = "English (US)",
volume = "105",
pages = "1079--1089",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "4",

}

TY - JOUR

T1 - Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition

AU - Tian, Xiaojun

AU - Zhang, Hang

AU - Xing, Jianhua

PY - 2013/8/20

Y1 - 2013/8/20

N2 - Epithelial 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-β treatment. We construct a mathematical model for the core regulatory network controlling TGF-β-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-β 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/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/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.

AB - Epithelial 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-β treatment. We construct a mathematical model for the core regulatory network controlling TGF-β-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-β 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/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-β/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.

UR - http://www.scopus.com/inward/record.url?scp=84883025658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883025658&partnerID=8YFLogxK

U2 - 10.1016/j.bpj.2013.07.011

DO - 10.1016/j.bpj.2013.07.011

M3 - Article

VL - 105

SP - 1079

EP - 1089

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 4

ER -