Intrinsic limits to gene regulation by global crosstalk Journal Article

Author(s): Friedlander, Tamar; Prizak, Roshan; Guet, Cǎlin C; Barton, Nicholas H; Tkačik, Gašper
Article Title: Intrinsic limits to gene regulation by global crosstalk
Affiliation IST Austria
Abstract: Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. 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. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements.
Keywords: Evolvability, Regulatory networks
Journal Title: Nature Communications
Volume: 7
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2016-08-04
Start Page: Article number: 12307
Copyright Statement: CC-BY
DOI: 10.1038/ncomms12307
Notes: The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007–2013) under REA grant agreement number 291734 (T.F.), ERC grant number 250152 (N.B.) and Austrian Science Fund grant FWF P28844 (G.T.). We thank Rok Grah, Tiago Paixão, Georg Rieckh, Thomas Sokolowski and Marcin Zagorski for critical reading of the manuscript, and Dominik Schröder for valuable insights to our mean-field approximation.
Open access: yes (OA journal)