Why are cellular switches Boolean? General conditions for multistable genetic circuits

Macía, Javier; Widder, Stefanie; Solé, Ricard V.

doi:10.1016/j.jtbi.2009.07.019

Cited by 37 publications

(34 citation statements)

References 34 publications

(33 reference statements)

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“…The theoretical solution of introducing nonlinearity ARTICLE into a system composed of monomeric DNA-binding elements proposed the introduction of a pair of hypothetical transcription factors, each of which should be able to activate its own expression and simultaneously repress the transcription of the opposing transcription factor 29,30 . Such types of transcription factors would be very difficult to design.…”

Section: Resultsmentioning

confidence: 99%

A bistable genetic switch based on designable DNA-binding domains

et al. 2014

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Section: Resultsmentioning

confidence: 99%

A bistable genetic switch based on designable DNA-binding domains

et al. 2014

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“…The realization that mutually inhibiting TF-TF switches and mutually inhibiting miR-TF chimeric switches play an important role in cell-fate determination has led several groups to conduct theoretical studies of such circuits (17)(18)(19)(20)(21)(22). These studies have revealed that inclusion of transcription selfactivation can lead to the coexistence of three stable states (tristability) (17)(18)(19)(20). More specifically, the classical TF-TF toggle switch has two stable states, (0,1) and (1,0), where state (0) corresponds to relatively low expression (low concentration) and state (1) corresponds to relatively high expression (23).…”

Section: Significancementioning

confidence: 99%

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Jolly

Levine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

495

707

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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 microRNAbased 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 mesenchymalto-hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented. multistable decision circuit | partial EMT | cancer systems biology | microRNA modeling | metastable intermediate phenotypes U nderstanding cell-fate decisions during embryonic development and tumorigenesis remains a major research challenge in modern developmental and cancer biology (1). Over recent years, we have witnessed rapid progress in mapping the gene regulatory networks associated with cellular phenotype with applications to transitions from epithelial to mesenchymal modalities, to the differentiation of pluripotent stem cells into progenitor cells, to the existence and role of cancer stem-like cells (CSC), and to the production of induced pluripotent stem cells (iPSCs). Cellfate determinations in all of these examples involve changes in expression of various transcription factors (TFs) and microRNAs (miRNAs) that regulate cascades of regulatory networks, ultimately generating genome-wide gene-expression patterns and concomitant protein levels corresponding to a particular cell lineage (fate).The E/M Hybrid Phenotype. An archetypal example of cell-fate decisions concerns the forward and backward transitions between the epithelial (E) and mesenchymal (M) phenotypes (EMT and MET), transitions that play a critical role in embryonic deve...

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“…3A). Typically, self-activation on both sides of the toggle switch can render the circuit tristable (ternary or three-way) switch (52)(53)(54)(55). However, self-activation on one side can also render the circuit tristable for a wide range of parameters, as seen in both TF-TF toggle switches and miRNA-TF chimera toggle switches (36).…”

Section: The Unit Modulesmentioning

confidence: 99%

Toward Decoding the Principles of Cancer Metastasis Circuits

Jolly

Onuchic

et al. 2014

Cancer Research

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Understanding epithelial-mesenchymal transitions (EMT) during cancer metastasis remains a major challenge in modern biology. Recent observations of cell behavior together with progress in mapping the underlying regulatory genetic networks led to new understandings of carcinoma metastasis. It is now established that the genetic network that regulates the EMT also enables an epithelial-mesenchymal hybrid phenotype. These hybrid cells possess mixed carcinoma epithelial and mesenchymal characteristics that enable specialized capabilities such as collective cell migration. On the gene network perspective, a fourcomponent decision unit composed of two highly interconnected chimeric modules-the miR34/SNAIL and the miR200/ZEB mutual-inhibition feedback circuits-regulates the coexistence of and transitions between the different phenotypes. Here, we present a new tractable theoretical framework to model and decode the underlying principles governing the operation of the regulatory unit. Our approach connects the knowledge about intracellular pathways with observations of cellular behavior and advances toward understanding the logic of cancer decision-making. We found that the miR34/SNAIL module acts as an integrator while the miR200/ZEB module acts as a three-way switch. Consequently, the combined unit can give rise to three phenotypes (stable states): (i) a high miR200 and low ZEB, or (1, 0) state; (ii) a low miR200 and high ZEB, or (0, 1) state; and (iii) a medium miR200 and medium ZEB, or ( 1 / 2 , 1 / 2 ) state. We associate these states with the epithelial, mesenchymal, and hybrid phenotypes, respectively. We reflect on the consistency between our theoretical predictions and recent observations in several types of carcinomas and suggest new testable predictions.

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Why are cellular switches Boolean? General conditions for multistable genetic circuits

Cited by 37 publications

References 34 publications

A bistable genetic switch based on designable DNA-binding domains

A bistable genetic switch based on designable DNA-binding domains

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Toward Decoding the Principles of Cancer Metastasis Circuits

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