An Ovol2-Zeb1 Mutual Inhibitory Circuit Governs Bidirectional and Multi-step Transition between Epithelial and...

Area of Science:

• Cell Biology
• Systems Biology
• Developmental Biology

Background:

• Reversible epithelial-mesenchymal transition (EMT) is crucial for development and cancer metastasis.
• The underlying mechanisms of cellular plasticity during EMT are not fully understood.
• Existing models lack detailed insights into intermediate states and regulatory control.

Purpose of the Study:

• To elucidate the complex regulatory network governing EMT.
• To identify and characterize intermediate cell states during EMT.
• To investigate the role of transcriptional factor Ovol2 in modulating EMT robustness.

Main Methods:

• Systems biology approach integrating computational modeling and experimental validation.
• Analysis of regulatory interactions, including mutual inhibition between Ovol2 and Zeb1.
• Identification and characterization of distinct cellular phenotypes and their differentiation propensities.

Main Results:

• Multiple intermediate states contribute to EMT, with robustness modulated by Ovol2.
• A novel four-state system emerged from Ovol2-Zeb1 mutual inhibition, featuring two distinct intermediate phenotypes.
• Intermediate epithelial cells with bidirectional differentiation potential were identified, influenced by the balance of EMT factors.

Conclusions:

• Cellular plasticity in EMT can be controlled via multiple intermediate cell fates.
• Ovol2 plays a critical role in regulating EMT and selecting between intermediate states.
• The Ovol2-Zeb1 regulatory axis offers a new perspective on controlling cellular plasticity.