Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators
- David van Dijk1,2,3,5,7,
- Eilon Sharon2,3,5,8,
- Maya Lotan-Pompan2,3,
- Adina Weinberger2,3,
- Eran Segal2,3,6 and
- Lucas B. Carey4,6
- 1Department of Biological Sciences, Department of Systems Biology, Columbia University, New York, New York 10027, USA;
- 2Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel;
- 3Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel;
- 4Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- Corresponding authors: eran.segal{at}weizmann.ac.il, lucas.carey{at}upf.edu
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.212316.116.
- Received July 5, 2016.
- Accepted November 15, 2016.
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/.
