Cooperative Binding of Transcription Factors Promotes Bimodal Gene Expression Response

Pablo S Gutierrez,Diana Monteoliva,Luis Diambra,Frank Emmert-Streib

doi:10.1371/journal.pone.0044812

Pablo S Gutierrez, Diana Monteoliva + Show 2 more

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https://doi.org/10.1371/journal.pone.0044812

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Abstract

In the present work we extend and analyze the scope of our recently proposed stochastic model for transcriptional regulation, which considers an arbitrarily complex cis-regulatory system using only elementary reactions. Previously, we determined the role of cooperativity on the intrinsic fluctuations of gene expression for activating transcriptional switches, by means of master equation formalism and computer simulation. This model allowed us to distinguish between two cooperative binding mechanisms and, even though the mean expression levels were not affected differently by the acting mechanism, we showed that the associated fluctuations were different. In the present generalized model we include other regulatory functions in addition to those associated to an activator switch. Namely, we introduce repressive regulatory functions and two theoretical mechanisms that account for the biphasic response that some cis-regulatory systems show to the transcription factor concentration. We have also extended our previous master equation formalism in order to include protein production by stochastic translation of mRNA. Furthermore, we examine the graded/binary scenarios in the context of the interaction energy between transcription factors. In this sense, this is the first report to show that the cooperative binding of transcription factors to DNA promotes the “all-or-none” phenomenon observed in eukaryotic systems. In addition, we confirm that gene expression fluctuation levels associated with one of two cooperative binding mechanism never exceed the fluctuation levels of the other.

Highlights

At the transcriptional level gene expression is mainly controlled by the transcription factor (TF) proteins that bind to regulatory binding sites on the DNA [1,2]
We demonstrated what we previously suggested by examination of some regions of the parameters space [27]: that the stabilization cooperative binding mechanism always presents a level of fluctuation greater than or equal to the recruitment mechanism
E~6 corresponds to DGI~1 kcal/mol. This value is similar to the interaction energy between two l-repressor molecules [32] and a bit higher than the free energy associated with the cooperative binding of E2 proteins (DGI *0:7 kcal/mol.)

Summary

Introduction

At the transcriptional level gene expression is mainly controlled by the transcription factor (TF) proteins that bind to regulatory binding sites on the DNA [1,2]. The output varies smoothly with the input stimulus, whereas in the binary response, termed the ‘‘all-or-none’’ phenomenon, gene expression response mainly occurs at either low or high levels In the latter case, the resulting heterogeneous response of an ensemble of cells leads to a bimodal distribution of the protein level. The ‘‘all-ornone’’ gene expression response has been experimentally observed in some eukaryotic systems that do not involve bistability [4,5,12,13,14], where gene expression often occurs in stochastic bursts This suggests that the binary responses observed in inducible gene expression could be explained by fluctuations in the binding of TFs to DNA [6,15]

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Conclusion