title: Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators.
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.
authors.affiliation: Department of Biological Sciences, Department of Systems Biology, Columbia University, New York, New York 10027, USA.|Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: David
authors.identifier: 0000-0003-3911-9925
authors.initials: D
authors.lastname: van Dijk
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Eilon
authors.identifier: 0000-0002-1262-350X
authors.initials: E
authors.lastname: Sharon
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Lotan-Pompan
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Adina
authors.identifier: 0000-0003-2231-4687
authors.initials: A
authors.lastname: Weinberger
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, 76100 Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Eran
authors.identifier: 0000-0002-6859-1164
authors.initials: E
authors.lastname: Segal
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Lucas B
authors.identifier: 0000-0002-7245-6379
authors.initials: LB
authors.lastname: Carey
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors