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

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