Effect of Promoter Architecture on the Cell-to-Cell Variability in Gene Expression

Graduate Program in Biophysics and Structural Biology, Brandeis University, Waltham, Massachusetts,USA.
PLoS Computational Biology (Impact Factor: 4.62). 03/2011; 7(3):e1001100. DOI: 10.1371/journal.pcbi.1001100
Source: PubMed


Author Summary
Stochastic chemical kinetics provides a framework for modeling gene regulation at the single-cell level. Using this framework, we systematically investigate the effect of promoter architecture, that is, the number, quality and position of transcription factor binding sites, on cell-to-cell variability in transcription levels. We compare architectures resulting in transcriptional activation with those resulting in transcriptional repression. We start from simple activation and repression motifs with a single operator sequence, and explore the parameter regime for which the cell-to-cell variability is maximal. Using the same formalism, we then turn to more complicated architectures with more than one operator. We examine the effect of independent and cooperative binding, as well as the role of DNA mechanics for those architectures where DNA looping is relevant. We examine the interplay between operator strength and operator number, and we make specific predictions for single-cell mRNA-counting experiments with well characterized promoters. This theoretical approach makes it possible to find the statistical response of a population of cells to perturbations in the architecture of the promoter; it can be used to quantitatively test physical models of gene regulation in vivo, and as the basis of a more systematic approach to designing new promoter architectures.

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    • "Even in the unimodally expressed SUC2,3 the degree of cell-to-cell variability and of stochastic fluctuations in invertase expression could be quite large, on the basis of the presence of a TATA box and several transcription factor binding sites in its regulatory sequence.36 It has been recently found that both of these promoter architectural motifs may lead to elevated noise in gene expression in yeast.37–39 "
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    Communicative & integrative biology 01/2014; 7(1):e28230. DOI:10.4161/cib.28230
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    • "The positive effect of nucleosome occupancy on gene expression and saturation of gene expression can be explained by an equilibrium model which associates TC-bound nucleosome -2 with high transcriptional activity [46]. However, the negative effect of nucleosome occupancy on gene expression has to be incorporated into an irreversible chromatin remodeling rate. "
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    ABSTRACT: Nucleosomes, which are the basic packaging units of chromatin, are stably positioned in promoters upstream of most stress-inducible genes. These promoter nucleosomes are generally thought to repress gene expression due to exclusion; they prevent transcription factors from accessing their target sites on the DNA. However, the role of promoter nucleosomes that do not directly occlude transcription factor binding sites is not obvious. Here, we varied the stability of a non-occluding nucleosome positioned between a transcription factor binding site and the TATA box region in an inducible yeast promoter and measured downstream gene expression level. We found that gene expression level depends on the occupancy of the non-occluding nucleosome in a non-monotonic manner. We postulated that a non-occluding nucleosome can serve both as a vehicle of and a barrier to chromatin remodeling activity and built a quantitative, nonequilibrium model to explain the observed nontrivial effect of the intervening nucleosome. Our work sheds light on the dual role of nucleosome as a repressor and an activator and expands the standard model of gene expression to include irreversible promoter chromatin transitions.
    PLoS ONE 05/2013; 8(5):e63072. DOI:10.1371/journal.pone.0063072 · 3.23 Impact Factor
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