Intrinsic limits to gene regulation by global crosstalk

TL;DR

This paper develops a biophysical model to quantify the limits of gene regulation imposed by crosstalk, revealing how factors like TF specificity, cooperativity, and promoter architecture influence regulatory accuracy across genomes.

Contribution

It introduces a tractable model of global crosstalk in gene regulation, deriving bounds and analyzing how various mechanisms affect crosstalk severity.

Findings

Crosstalk severity can be analytically bounded based on gene number and binding site similarity.

Strong cooperativity reduces crosstalk significantly.

Joint regulation by activators and repressors does not necessarily decrease crosstalk.

Abstract

Gene regulation relies on the specificity of transcription factor (TF) - DNA interactions. In equilibrium, limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF-DNA interactions or remains erroneously inactive. We present a tractable biophysical model of global crosstalk, where many genes are simultaneously regulated by many TFs. We show that in the simplest regulatory scenario, a lower bound on crosstalk severity can be analytically derived solely from the number of (co)regulated genes and a suitable parameter that describes binding site similarity. Estimates show that crosstalk could present a significant challenge for organisms with low-specificity TFs, such as metazoans, unless they use appropriate regulation schemes. Strong cooperativity substantially decreases crosstalk, while joint regulation by activators and repressors, surprisingly, does not; moreover, certain microscopic details about promoter architecture emerge as globally important determinants of crosstalk strength. Our results suggest that crosstalk imposes a new type of global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints acting at the level of individual gene regulatory elements.