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

Abstract

Reversible epithelial-to-mesenchymal transition (EMT) is central to tissue development, epithelial stemness, and cancer metastasis. While many regulatory elements have been identified to induce EMT, the complex process underlying such cellular plasticity remains poorly understood. Utilizing a systems biology approach integrating modeling and experiments, we found multiple intermediate states contributing to EMT and that the robustness of the transitions is modulated by transcriptional factor Ovol2. In particular, we obtained evidence for a mutual inhibition relationship between Ovol2 and EMT inducer Zeb1, and observed that adding this regulation generates a novel four-state system consisting of two distinct intermediate phenotypes that differ in differentiation propensities and are favored in different environmental conditions. We identified epithelial cells that naturally exist in an intermediate state with bidirectional differentiation potential, and found the balance between EMT-promoting and -inhibiting factors to be critical in achieving and selecting between intermediate states. Our analysis suggests a new design principle in controlling cellular plasticity through multiple intermediate cell fates and underscores the critical involvement of Ovol2 and its associated molecular regulations.

Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric

“…Moreover, the hybrid E/M phenotype has been tacitly assumed to be metastable or transient [11]. Recent studies, however, have challenged this assumption by demonstrating that a hybrid E/M phenotype can be stably maintained in vitro at a single-cell level, especially under the influence of factors such as GRHL2 and OVOL2 that contribute to the stability of a hybrid E/M phenotype [12–14]. These factors are referred to as ‘phenotypic stability factors’ (PSFs), and their elevated expression, indicative of a stable hybrid E/M levels, are associated with worse patient survival [12].…”

Overexpression of Transcription Factor Ovol2 in Epidermal Progenitor Cells Results in Skin Blistering

“…To ask whether altered keratin expression is a cell-autonomous and self-sufficient effect of Ovol2, we performed RNA-seq analysis to probe Ovol2-induced changes in a heterologous system, MCF10A mammary epithelial cells that normally express K5/K14 (Hong et al, 2015). Ovol2 overexpression resulted in a significant reduction of KRT5/KRT14 and an increase of KRT6/KRT16 expression (Figure 2g), recapitulating the changes detected in BT epidermis.…”

Quantifying the landscape and kinetic paths for epithelial–mesenchymal transition from a core circuit

“…However, more complex networks 6,23,46 involve more molecular details, which may influence the dynamics of EMT system. For example, a recent work suggests that the mutual repression between OVOL2 and ZEB are critical to the multi-step EMT transitions 23 . Understanding the mechanisms of those multi-step transitions in the larger networks using landscape theory will be topics of future studies.…”

“…the synthesis or degradation rate of genes, or regulatory strength among genes) and the noise level are varied. The landscape theory as a metaphor has been used as a pictorial illustration for EMT transitions previously 6,23 . However, a more rigorous and quantitative study of EMT networks using the landscape theory is needed to gain more insights into the EMT system.…”