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Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators

Transcription factors (TFs) are key mediators that propagate extracellular and intracellular signals through to changes in gene expression profiles. However, the rules by which promoters decode the amount of active TF into target gene expression are not well understood. To determine the mapping betw...

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Autores principales: van Dijk, David, Sharon, Eilon, Lotan-Pompan, Maya, Weinberger, Adina, Segal, Eran, Carey, Lucas B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204347/
https://www.ncbi.nlm.nih.gov/pubmed/27965290
http://dx.doi.org/10.1101/gr.212316.116
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author van Dijk, David
Sharon, Eilon
Lotan-Pompan, Maya
Weinberger, Adina
Segal, Eran
Carey, Lucas B.
author_facet van Dijk, David
Sharon, Eilon
Lotan-Pompan, Maya
Weinberger, Adina
Segal, Eran
Carey, Lucas B.
author_sort van Dijk, David
collection PubMed
description Transcription factors (TFs) are key mediators that propagate extracellular and intracellular signals through to changes in gene expression profiles. However, the rules by which promoters decode the amount of active TF into target gene expression are not well understood. To determine the mapping between promoter DNA sequence, TF concentration, and gene expression output, we have conducted in budding yeast a large-scale measurement of the activity of thousands of designed promoters at six different levels of TF. We observe that maximum promoter activity is determined by TF concentration and not by the number of binding sites. Surprisingly, the addition of an activator site often reduces expression. A thermodynamic model that incorporates competition between neighboring binding sites for a local pool of TF molecules explains this behavior and accurately predicts both absolute expression and the amount by which addition of a site increases or reduces expression. Taken together, our findings support a model in which neighboring binding sites interact competitively when TF is limiting but otherwise act additively.
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spelling pubmed-52043472017-07-01 Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators van Dijk, David Sharon, Eilon Lotan-Pompan, Maya Weinberger, Adina Segal, Eran Carey, Lucas B. Genome Res Research Transcription factors (TFs) are key mediators that propagate extracellular and intracellular signals through to changes in gene expression profiles. However, the rules by which promoters decode the amount of active TF into target gene expression are not well understood. To determine the mapping between promoter DNA sequence, TF concentration, and gene expression output, we have conducted in budding yeast a large-scale measurement of the activity of thousands of designed promoters at six different levels of TF. We observe that maximum promoter activity is determined by TF concentration and not by the number of binding sites. Surprisingly, the addition of an activator site often reduces expression. A thermodynamic model that incorporates competition between neighboring binding sites for a local pool of TF molecules explains this behavior and accurately predicts both absolute expression and the amount by which addition of a site increases or reduces expression. Taken together, our findings support a model in which neighboring binding sites interact competitively when TF is limiting but otherwise act additively. Cold Spring Harbor Laboratory Press 2017-01 /pmc/articles/PMC5204347/ /pubmed/27965290 http://dx.doi.org/10.1101/gr.212316.116 Text en © 2017 van Dijk et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
van Dijk, David
Sharon, Eilon
Lotan-Pompan, Maya
Weinberger, Adina
Segal, Eran
Carey, Lucas B.
Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title_full Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title_fullStr Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title_full_unstemmed Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title_short Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
title_sort large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204347/
https://www.ncbi.nlm.nih.gov/pubmed/27965290
http://dx.doi.org/10.1101/gr.212316.116
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