2013/07/25 by Xiao-Jun Tian, Xiao‐Jun Tian, Hang Zhang +1
Biochemistry, Genetics and Molecular Biology · Chemistry · #Biochemistry #Biology #Biophysics #Bistability #Cell biology #Cellular Mechanics and Interactions #Chemistry #Epithelial–mesenchymal transition #Gene #Gene Regulatory Network Analysis #Materials science #Mesenchymal stem cell #Optoelectronics #Single-cell and spatial transcriptomics #Transforming growth factor #Transition (genetics) #q-bio.MN
paper · pdf · doi:10.1016/j.bpj.2013.07.011
published as Biophys J 105, 1079 (2013) · 32 pages, 8 figures, accepted by Biophysical Journal
arxiv created 2013/07/25 · openalex publication_date 2013/08/01 · arxiv updated 2017/07/26 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
Epithelial to mesenchymal transition (EMT) plays important roles in embryonic development, tissue regeneration and cancer metastasis. While several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-βtreatment. 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 that an epithelial cell first transits to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-βstimulation. 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, while 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.