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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    ABSTRACT: From the physiological and anatomical point of view, the lateral visual field of the human operator is approximately 180�. Although a number of visual functions including visual acuity and the ability to detect light decrease in the peripheral regions, a normal observer generally makes discriminations out to 80� on either side of the midline and beyond. Such data as these are obtained primarily from standard experiments in which the subject, seated comfortably in an experimental room reports on the presence and nature of stimuli presented to his peripheral visual field. A different situation arises, however, When similar data are taken under non-standard laboratory conditions. If the subject is under physical or emotional stress, frightened, inexperienced, under the effects of drugs, etc., a decrement in the ability to detect peripheral stimuli is observed, This phenomenon has given rise to the concept of the functional visual field implying that although the anatomical and physiological mechanisms are present, stimuli presented to the periphery cannot be detected, or are detected at a lower level of efficiency, under conditions of stress. In connection with an experiment designed to determine the physiological effects of severe water loss as a result of heat stress, an opportunity was provided to also test the subject's ability to detect peripherally presented stimuli. Eight subjects worked on a standard treadmill according to a 20 minutes on-off duty cycle for six hours. The speed and inclination of the treadmill were adjusted so as to produce, on different days, either 5% or 2.5% weight loss. Half the subjects were male, half female, half lean and half obese. In addition, at the end of the 6 hour session, a maximum performance test was given to each subject. Data were obtained not only on the ability to detect peripheral thresholds, but also on central reaction time. The results indicate no effect whatsoever of any of the conditions of the experiment on any - of the measurements taken. These data are in marked contrast to those of previous studies in which even the slightest changes in stimulus conditions produced loss of peripheral discrimination. The discrepancy between this and previous studies is attributed to the fact that the subjects had previous training in the use of the apparatus, that they were highly motivated, and that they were required to respond only for short prearranged duty cycles.
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