Dec 28, 2016

Population Heterogeneity in the Epithelial to Mesenchymal Transition Is Controlled by NFAT and Phosphorylated Sp1

PLoS Computational Biology
Russell GouldJonathan T Butcher

Abstract

Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor β (TGF-β) family members, and restricted by vascular endothelial growth factor family members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing TGF-β induced EMT to better understand the operational hierarchy of this complex molecular program. We used ordinary differential equations (ODEs) to describe the transcriptional and post-translational regulatory events driving EMT. Model parameters were estimated from multiple data sets using multiobjective optimization, in combination with cross-validation. TGF-β exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following vascular endothelial growth factor A (VEGF-A) exposure. Simulations predicted that the transcription factors phosphorylated SP1 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also predicted...Continue Reading

  • References67
  • Citations3

References

  • References67
  • Citations3

Mentioned in this Paper

Biological Markers
Embryo
Neuro-Oncological Ventral Antigen 2
Establishment and Maintenance of Localization
Real-Time Polymerase Chain Reaction
Recombinant Transforming Growth Factor
JUN gene
In Silico
Study
JUND gene

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