Pirone, J. R. & Elston, T. C. Fluctuations in transcription factor binding can explain the graded and binary responses observed in inducible gene expression. J. Theor. Biol. 226, 111-121

Department of Mathematics, University of North Carolina at Chapel Hill, North Carolina, United States
Journal of Theoretical Biology (Impact Factor: 2.12). 02/2004; 226(1):111-21. DOI: 10.1016/j.jtbi.2003.08.008
Source: PubMed


Inducible genes are expressed in the presence of an external stimulus. Individual cells may exhibit either a binary or graded response to such signals. It has been hypothesized that the chemical kinetics of transcription factor/DNA interactions can account for both these scenarios (EMBO J. 9(9) (1990) 2835; BioEssays 14(5) (1992) 341). To explore this question, we have conducted work based on the experimental results of Fiering et al. (Genes Dev. 4 (10) (1990) 1823). In these experiments, three upstream NF-AT binding sites control transcription of the lacZ gene, which codes for the enzyme beta-Galactosidase. The experimental data show a binary response for this system. We consider the effects of fluctuations in NF-AT binding on the response of the system. Our modeling results are in good qualitative agreement with the experimental data, and illustrate how the binary and graded responses can stem from the same underlying mechanism.

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    • "Ferrell & Machleder (1998) present data that suggest that the latter, all-or-none response, is what occurs in the MAPK cascade . Studies suggest that the all-or-none behavior is also exhibited in gene induction and protein expression (Pirone and Elston, 2004; Zhang et al., 2006). Biologically based mathematical models are increasingly used to predict the shape of the dose response curve, specifically at low environmentally-relevant exposure levels. "
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    ABSTRACT: The mitogen activated protein kinase (MAPK) cascade is a three-tiered phosphorylation cascade that is ubiquitously expressed among eukaryotic cells. Its primary function is to propagate signals from cell surface receptors to various cytosolic and nuclear targets. Recent studies have demonstrated that the MAPK cascade exhibits an all-or-none response to graded stimuli. This study quantitatively investigates MAPK activation in Xenopus oocytes using both empirical and biologically-based mechanistic models. Empirical models can represent overall tissue MAPK activation in the oocytes. However, these models lack description of key biological processes and therefore give no insight into whether the cellular response occurs in a graded or all-or-none fashion. To examine the propagation of cellular MAPK all-or-none activation to overall tissue response, mechanistic models in conjunction with Monte Carlo simulations are employed. An adequate description of the dose response relationship of MAPK activation in Xenopus oocytes is achieved. Furthermore, application of these mechanistic models revealed that the initial receptor-ligand binding rate contributes to the cells' ability to exhibit an all-or-none MAPK activation response, while downstream activation parameters contribute more to the magnitude of activation. These mechanistic models enable us to identify key biological events which quantitatively impact the shape of the dose response curve, especially at low environmentally relevant doses.
    Dose-Response 07/2010; 8(3):347-67. DOI:10.2203/dose-response.09-017.Luke · 1.22 Impact Factor
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    • "Spontaneous transitions between an active and an inactive gene state can significantly increase the expression variability (Raser and O'Shea, 2004; Bar-Even et al, 2006), and give rise to transcriptional bursts that have also been observed experimentally (Chubb et al, 2006; Raj et al, 2006). In principle, the bimodal expression pattern of IL-4 could arise from such transitions, as long as mRNA and protein are sufficiently short lived to be completely removed from the cell between successive bursts (Pirone and Elston, 2004). In this scenario, only a fraction of cells would express the protein at a given point in time although each cell, at some point, would produce IL-4. "
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    ABSTRACT: Although cell-to-cell variability has been recognized as an unavoidable consequence of stochasticity in gene expression, it may also serve a functional role for tuning physiological responses within a cell population. In the immune system, remarkably large variability in the expression of cytokine genes has been observed in homogeneous populations of lymphocytes, but the underlying molecular mechanisms are incompletely understood. Here, we study the interleukin-4 gene (il4) in T-helper lymphocytes, combining mathematical modeling with the experimental quantification of expression variability and critical parameters. We show that a stochastic rate-limiting step upstream of transcription initiation, but acting at the level of an individual allele, controls il4 expression. Only a fraction of cells reaches an active, transcription-competent state in the transient time window determined by antigen stimulation. We support this finding by experimental evidence of a previously unknown short-term memory that was predicted by the model to arise from the long lifetime of the active state. Our analysis shows how a stochastic mechanism acting at the chromatin level can be integrated with transcriptional regulation to quantitatively control cell-to-cell variability.
    Molecular Systems Biology 04/2010; 6(1):359. DOI:10.1038/msb.2010.13 · 10.87 Impact Factor
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    • "By differentially controlling the activation of different genes, oscillation frequency may direct cells along specific developmental pathways. Although it was experimentally shown that intracellular Ca 2+ oscillations increase the efficiency and specificity of gene expression, little theoretical study on the activation of transcription factor modulated by intracellular Ca 2+ oscillations [21] [22] has been carried out. Specially, it is not clear how the intracellular Ca 2+ oscillations mediate the efficiency and specificity of gene expression within the framework of kinetics. "
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    ABSTRACT: This work presents both deterministic and stochastic models of genetic expression modulated by intracellular calcium (Ca2+) oscillations, based on macroscopic differential equations and chemical Langevin equations, respectively. In deterministic case, the oscillations of intracellular Ca2+ decrease the effective Ca2+ threshold for the activation of transcriptional activator (TF-A). The average activation of TF-A increases with the increase of the average amplitude of intracellular Ca2+ oscillations, but decreases with the increase of the period of intracellular Ca2+ oscillations, which are qualitatively consistent with the experimental results on the gene expression in lymphocytes. In stochastic case, it is found that a large internal fluctuation of the biochemical reaction can enhance gene expression efficiency specifically at a low level of external stimulations or at a small rate of TF-A dimer phosphorylation activated by Ca2+, which reduces the threshold of the average intracellular Ca2+ concentration for gene expression.
    Biophysical Chemistry 09/2007; 129(1):49-55. DOI:10.1016/j.bpc.2007.05.006 · 1.99 Impact Factor
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