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Normative models of enhancer function

Rok Grah, Benjamin Zoller, View ORCID ProfileGašper Tkačik
doi: https://doi.org/10.1101/2020.04.08.029405
Rok Grah
*Institute of Science and Technology Austria, AT-3400 Klosterneuburg, Austria
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Benjamin Zoller
†Princeton University, NJ 08544 Princeton, USA; Institut Pasteur, FR-75015 Paris, France
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Gašper Tkačik
*Institute of Science and Technology Austria, AT-3400 Klosterneuburg, Austria
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  • ORCID record for Gašper Tkačik
  • For correspondence: gtkacik@ist.ac.at
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Abstract

In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene expression levels that is compatible with in vivo and in vitro bio-physical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In non-equilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal non-equilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in non-equilibrium models is in a tradeoff with gene expression noise, predicting bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space to a much smaller subspace that optimally realizes biological function prior to inference from data, our normative approach holds promise for mathematical models in systems biology.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 09, 2020.
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Normative models of enhancer function
Rok Grah, Benjamin Zoller, Gašper Tkačik
bioRxiv 2020.04.08.029405; doi: https://doi.org/10.1101/2020.04.08.029405
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Normative models of enhancer function
Rok Grah, Benjamin Zoller, Gašper Tkačik
bioRxiv 2020.04.08.029405; doi: https://doi.org/10.1101/2020.04.08.029405

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