title: Intrinsic limits to gene regulation by global crosstalk.
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.
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors.forename: Tamar
authors.initials: T
authors.lastname: Friedlander
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors.forename: Roshan
authors.initials: R
authors.lastname: Prizak
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors.forename: Călin C
authors.initials: CC
authors.lastname: Guet
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Barton
authors.affiliation: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors.forename: Gašper
authors.initials: G
authors.lastname: Tkačik
mesh_terms: D001665:Binding Sites / Q000235:genetics; D056890:Eukaryota / Q000235:genetics; D005786:Gene Expression Regulation; D008957:Models, Genetic; D011387:Prokaryotic Cells / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D014157:Transcription Factors