title: MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination.
abstract: Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules--the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. Here, we used detailed modeling of microRNA-based regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states--(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)--with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expression measurements in collectively migrating cells) and explains the lack of observed mesenchymal-to-hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented.
authors.affiliation: Center for Theoretical Biological Physics and Departments of Bioengineering, Physics and Astronomy, Chemistry, and Biochemistry and Cell Biology, Rice University, Houston, TX 77005-1827.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lu
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: cancer systems biology; metastable intermediate phenotypes; microRNA modeling; multistable decision circuit; partial EMT