title: 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.
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.|Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Catherine Ha
authors.initials: CH
authors.lastname: Ta
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.|Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Villarreal-Ponce
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, California, United States of America.|Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Nie
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, California, United States of America.|Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D019295:Computational Biology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D025461:Feedback, Physiological; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors