Multistability in the lactose utilization network of Escherichia coli

Abstract

Multistability, the capacity to achieve multiple internal states in response to a single set of external inputs, is the defining characteristic of a switch. Biological switches are essential for the determination of cell fate in multicellular organisms, the regulation of cell-cycle oscillations during mitosis and the maintenance of epigenetic traits in microbes. The multistability of several natural and synthetic systems has been attributed to positive feedback loops in their regulatory networks. However, feedback alone does not guarantee multistability. The phase diagram of a multistable system, a concise description of internal states as key parameters are varied, reveals the conditions required to produce a functional switch. Here we present the phase diagram of the bistable lactose utilization network of Escherichia coli. We use this phase diagram, coupled with a mathematical model of the network, to quantitatively investigate processes such as sugar uptake and transcriptional regulation in vivo. We then show how the hysteretic response of the wild-type system can be converted to an ultrasensitive graded response. The phase diagram thus serves as a sensitive probe of molecular interactions and as a powerful tool for rational network design.

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

“…Many areas of research make use of the concept of switching between alternative attractors, e.g. in ecology, 68 developmental biology, 69 gene regulation studies on the Lac operon, 8 systems biology, 70 epigenetic regulation 13 and haematology. [10][11][12] All models used in these fields share the key feature of cooperative (i.e., nonlinear) positive feedback that fosters the formation of multiple attractors.…”

“…Mathematical models have revealed nonlinearity in genetic networks that allow cells to switch between states. Examples are the Lac operon 8 and cells of the haematopoietic lineage. [9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models.…”

Multistability and oscillations in genetic control of metabolism

“…The analysis predicts nutrientinduced bistability, which was experimentally observed in the lactose operon [19], and also suggests the emergence of nutrient-induced oscillations.…”

Computational approaches for modeling regulatory cellular networks

“…Hence, the dynamics of stochastic systems cannot be predicted with complete certainties from the initial conditions. The biochemical fluctuations or `noise' inherent in such stochastic systems are often exploited in cellular functions, resulting in spontaneous switching from one biochemical state to another [21][22][23][24].…”

“…Hence, the dynamics of stochastic systems cannot be predicted with complete certainties from the initial conditions. The biochemical fluctuations or `noise' inherent in such stochastic systems are often exploited in cellular functions, resulting in spontaneous switching from one biochemical state to another [21][22][23][24].Under the classification of deterministic and stochastic models, the cell can be viewed as either a spatially homogeneous or a heterogeneous reactor. The vast majority of models that have been constructed for signaling networks are based on solution kinetics in which spatial The exchange of molecules between compartments is modeled as a flux, which can either be determined from a priori knowledge or be fitted to empirical observations [28].…”