Stochastic proofreading mechanism alleviates crosstalk in transcriptional regulation

TL;DR

This paper introduces a non-equilibrium kinetic proofreading mechanism to reduce crosstalk in transcriptional regulation, improving specificity at the cost of increased gene expression noise, supported by information theory analysis.

Contribution

It proposes a novel non-equilibrium proofreading scheme to suppress transcriptional crosstalk, addressing limitations of traditional equilibrium models.

Findings

Proofreading reduces crosstalk in transcriptional regulation.

Increased noise is a tradeoff for higher specificity.

Optimal proofreading architectures are favored under certain conditions.

Abstract

Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that non-cognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibrium models of TF binding, and propose an alternative non-equilibrium scheme that implements kinetic proofreading to suppress erroneous initiation. This proposal is consistent with the observed covalent modifications of the transcriptional apparatus and would predict increased noise in gene expression as a tradeoff for improved specificity. Using information theory, we quantify this tradeoff to find when optimal proofreading architectures are favored over their equilibrium counterparts.