Intrinsic limits to gene regulation by global crosstalk

Friedlander, Tamar and Prizak, Roshan and Guet, Cǎlin C and Barton, Nicholas H and Tkačik, Gašper (2016) Intrinsic limits to gene regulation by global crosstalk. Nature Communications, 7. Article number: 12307 . ISSN 2041-1723

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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.

Item Type: Article
DOI: 10.1038/ncomms12307
Uncontrolled Keywords: Evolvability, Regulatory networks
Subjects: 500 Science > 570 Life sciences; biology > 576 Genetics and evolution
Research Group: Barton Group
Guet Group
Tkacik Group
SWORD Depositor: Sword Import User
Depositing User: Sword Import User
Date Deposited: 16 Aug 2016 12:07
Last Modified: 30 Aug 2017 07:50

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