Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate

Schultz, Daniel; Lu, Mingyang; Stavropoulos, Trevor; Onuchic, José N.; Ben‐Jacob, Eshel

doi:10.1038/srep01668

Cited by 27 publications

(51 citation statements)

References 42 publications

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“…This approach enables us to investigate the effect of the number of the microRNA binding sites on the mRNA. We found that the [miR-34/SNAIL] module is a monostable circuit that acts as a noise-buffering integrator, reminiscent of the bacterial sporulation sensing system (25)(26)(27). The [miR-200/ZEB] module was found to be a tristable circuit that acts as a ternary switch.…”

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.

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487

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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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.

Self Cite

487

707

View full text Add to dashboard Cite

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“…However, recent work Kuchina et al (2011) showed that slow progression to sporulation and excursions to competence occurs independently and concurrently up to a certain irreversible decision point, and the choice of the phenotype depends on the outcome of a “molecular race” between the two independently progressing differentiation programs: whichever program reaches the decision point first, wins. On the other hand, the decision circuit itself appears to have non-trivial oscillatory that transiently open so-called “windows of opportunity” for competence Schultz et al (2013).…”

Section: Stochasticity In Cell Biologymentioning

confidence: 99%

Noise in biology

2014

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Noise permeates biology on all levels, from the most basic molecular, sub-cellular processes to the dynamics of tissues, organs, organisms, and populations. The functional roles of noise in biological processes can vary greatly. Along with standard, entropy-increasing effects of producing random mutations, diversifying phenotypes in isogenic populations, limiting information capacity of signaling relays, it occasionally plays more surprising constructive roles by accelerating the pace of evolution, providing selective advantage in dynamic environments, enhancing intracellular transport of biomolecules and increasing information capacity of signaling pathways. This short review covers the recent progress in understanding mechanisms and effects of fluctuations in biological systems of different scales and the basic approaches to their mathematical modeling.

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“…The present theoretical approach brings to light that Hes1 oscillation actually keeps in balance a labile proliferation state and two competing cell fate outputs associated with distinct Hes1-high and Hes1-low cell cycle arrest states, the outcome of which depends on the relative sensitivity of neighboring cells to extracellular signaling cues stabilizing Hes1 expression at either high or low levels. Hes1 oscillation thus maintains a highly dynamic precommitment state that is well-equipped with a wealth of decision-making properties, such as decision gates through signal timing sensitivity (Schultz et al, 2013;Pfeuty and Kaneko, 2014) or population-level decisions finely tuned by synchronization/ desynchronization mechanisms (Lewis, 2003;Suzuki et al, 2011;Wang et al, 2011). For the latter, lateral inhibition constitutes a powerful intercellular coupling mechanism for promoting reliable cell fate decisions while maintaining cell type diversity .…”

Section: Developmental Cell Fate Decisions Through Oscillatory Dynamimentioning

confidence: 99%

A computational model for the coordination of neural progenitor self-renewal and differentiation through Hes1 dynamics

Pfeuty

2015

Development

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Proper tissue development requires that stem/progenitor cells precisely coordinate cell division and differentiation in space and time. NotchHes1 intercellular signaling, which affects both differentiation and cell cycle progression and directs cell fate decisions at various developmental stages in many cell types, is central to this process. This study explored whether the pattern of connections among the cell cycle regulatory module, the Notch effector Hes1 and the proneural factor Ngn2 could explain salient aspects of cell fate determination in neural progenitors. A mathematical model that includes mutual interactions between Hes1, Ngn2 and G1-phase regulators was constructed and simulated at the single-and two-cell levels. By differentially regulating G1-phase progression, Hes1 and Ngn2 are shown to induce two contrasting cell cycle arrest states in early and late G1, respectively. Indeed, steady Hes1 overexpression promotes reversible quiescence by downregulating activators of G0/G1 exit and Ngn2. Ngn2 also downregulates activators of G0/G1 exit, but cooperates with Cip/Kip proteins to prevent G1/S transit, whereby it promotes G1-phase lengthening and, ultimately, contributes to reinforcing an irreversible late G1 arrest coincident with terminal differentiation. In this scheme, Hes1 oscillation in single cells is able to maintain a labile proliferation state in dynamic balance with two competing cell fate outputs associated with Hes1-mediated and Ngn2-mediated cell cycle arrest states. In Delta/Notch-connected cells, Hes1 oscillations and a lateral inhibition mechanism combine to establish heterogeneous Hes1, Ngn2 and cell cycle dynamics between proliferating neural progenitors, thereby increasing the chances of asymmetric cell fate decisions and improving the reliability of commitment to differentiation.

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Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate

Cited by 27 publications

References 42 publications

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

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

Noise in biology

A computational model for the coordination of neural progenitor self-renewal and differentiation through Hes1 dynamics

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