10,673 research outputs found
Phenotypic Variation and Bistable Switching in Bacteria
Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.
Fitness and entropy production in a cell population dynamics with epigenetic phenotype switching
Motivated by recent understandings in the stochastic natures of gene
expression, biochemical signaling, and spontaneous reversible epigenetic
switchings, we study a simple deterministic cell population dynamics in which
subpopulations grow with different rates and individual cells can
bi-directionally switch between a small number of different epigenetic
phenotypes. Two theories in the past, the population dynamics and
thermodynamics of master equations, separatedly defined two important concepts
in mathematical terms: the {\em fitness} in the former and the (non-adiabatic)
{\em entropy production} in the latter. Both play important roles in the
evolution of the cell population dynamics. The switching sustains the
variations among the subpopulation growth thus continuous natural selection. As
a form of Price's equation, the fitness increases with () natural selection
through variations and a positive covariance between the per capita
growth and switching, which represents a Lamarchian-like behavior. A negative
covariance balances the natural selection in a fitness steady state | "the red
queen" scenario. At the same time the growth keeps the proportions of
subpopulations away from the "intrinsic" switching equilibrium of individual
cells, thus leads to a continous entropy production. A covariance, between the
per capita growth rate and the "chemical potential" of subpopulation,
counter-acts the entropy production. Analytical results are obtained for the
limiting cases of growth dominating switching and vice versa.Comment: 16 page
Exploration-exploitation tradeoffs dictate the optimal distributions of phenotypes for populations subject to fitness fluctuations
We study a minimal model for the growth of a phenotypically heterogeneous
population of cells subject to a fluctuating environment in which they can
replicate (by exploiting available resources) and modify their phenotype within
a given landscape (thereby exploring novel configurations). The model displays
an exploration-exploitation trade-off whose specifics depend on the statistics
of the environment. Most notably, the phenotypic distribution corresponding to
maximum population fitness (i.e. growth rate) requires a non-zero exploration
rate when the magnitude of environmental fluctuations changes randomly over
time, while a purely exploitative strategy turns out to be optimal in two-state
environments, independently of the statistics of switching times. We obtain
analytical insight into the limiting cases of very fast and very slow
exploration rates by directly linking population growth to the features of the
environment.Comment: 13 pages, 5 figure
Unrelated toxin-antitoxin systems cooperate to induce persistence.
Persisters are drug-tolerant bacteria that account for the majority of bacterial infections. They are not mutants, rather, they are slow-growing cells in an otherwise normally growing population. It is known that the frequency of persisters in a population is correlated with the number of toxin-antitoxin systems in the organism. Our previous work provided a mechanistic link between the two by showing how multiple toxin-antitoxin systems, which are present in nearly all bacteria, can cooperate to induce bistable toxin concentrations that result in a heterogeneous population of slow- and fast-growing cells. As such, the slow-growing persisters are a bet-hedging subpopulation maintained under normal conditions. For technical reasons, the model assumed that the kinetic parameters of the various toxin-antitoxin systems in the cell are identical, but experimental data indicate that they differ, sometimes dramatically. Thus, a critical question remains: whether toxin-antitoxin systems from the diverse families, often found together in a cell, with significantly different kinetics, can cooperate in a similar manner. Here, we characterize the interaction of toxin-antitoxin systems from many families that are unrelated and kinetically diverse, and identify the essential determinant for their cooperation. The generic architecture of toxin-antitoxin systems provides the potential for bistability, and our results show that even when they do not exhibit bistability alone, unrelated systems can be coupled by the growth rate to create a strongly bistable, hysteretic switch between normal (fast-growing) and persistent (slow-growing) states. Different combinations of kinetic parameters can produce similar toxic switching thresholds, and the proximity of the thresholds is the primary determinant of bistability. Stochastic fluctuations can spontaneously switch all of the toxin-antitoxin systems in a cell at once. The spontaneous switch creates a heterogeneous population of growing and non-growing cells, typical of persisters, that exist under normal conditions, rather than only as an induced response. The frequency of persisters in the population can be tuned for a particular environmental niche by mixing and matching unrelated systems via mutation, horizontal gene transfer and selection
A stochastic and dynamical view of pluripotency in mouse embryonic stem cells
Pluripotent embryonic stem cells are of paramount importance for biomedical
research thanks to their innate ability for self-renewal and differentiation
into all major cell lines. The fateful decision to exit or remain in the
pluripotent state is regulated by complex genetic regulatory network. Latest
advances in transcriptomics have made it possible to infer basic topologies of
pluripotency governing networks. The inferred network topologies, however, only
encode boolean information while remaining silent about the roles of dynamics
and molecular noise in gene expression. These features are widely considered
essential for functional decision making. Herein we developed a framework for
extending the boolean level networks into models accounting for individual
genetic switches and promoter architecture which allows mechanistic
interrogation of the roles of molecular noise, external signaling, and network
topology. We demonstrate the pluripotent state of the network to be a broad
attractor which is robust to variations of gene expression. Dynamics of exiting
the pluripotent state, on the other hand, is significantly influenced by the
molecular noise originating from genetic switching events which makes cells
more responsive to extracellular signals. Lastly we show that steady state
probability landscape can be significantly remodeled by global gene switching
rates alone which can be taken as a proxy for how global epigenetic
modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure
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