Analysis of Combinatorial cis-Regulation in Synthetic and Genomic Promoters
By Jason Gertz, E. Siggia, Barak A. Cohen. Nature, 2008
661 citations recorded by the source corpus.
Transcription factor binding sites are being discovered at a rapid pace. It is now necessary to turn attention towards understanding how these sites work in combination to influence gene expression. Quantitative models that accurately predict gene expression from promoter sequence will be a crucial part of solving this problem. Here we present such a model, based on the analysis of synthetic promoter libraries in yeast (Saccharomyces cerevisiae). Thermodynamic models based only on the equilibrium binding of transcription factors to DNA and to each other captured a large fraction of the variation in expression in every library. Thermodynamic analysis of these libraries uncovered several phenomena in our system, including cooperativity and the effects of weak binding sites. When applied to the S. cerevisiae genome, a model of repression by Mig1 (which was trained on synthetic promoters) predicts a number of Mig1-regulated genes that lack significant Mig1-binding sites in their promoters. The success of the thermodynamic approach suggests that the information encoded by combinations of cis-regulatory sites is interpreted primarily through simple protein–DNA and protein–protein interactions, with complicated biochemical reactions—such as nucleosome modifications—being downstream events. Quantitative analyses of synthetic promoter libraries will be an important tool in unravelling the rules underlying combinatorial cis-regulation.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a3de4510dd5d77e88b45f772655e16f9c04b5a3f
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In Genetics
In Molecular Biology
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Citations in the corpus
- Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters (2012, positive): “Several medium-scale 1–3 and large-scale 4–6 libraries have been created in bacteria and yeast in which transcription regulatory elements were randomly ligated or muta-genized and the expression of the resulting promoters was measured.”
- DIVERSITY-BASED, MODEL-GUIDED CONSTRUCTION OF SYNTHETIC GENE NETWORKS WITH PREDICTED FUNCTIONS (2009, neutral): “Promoter libraries have been created using DNA-shuffling/combinatorial approache”
- Transcriptional enhancers: from properties to genome-wide predictions (2014, neutral): “Such analyses will also benefit enormously from the ability to test enhancer variants 126,127 or synthetic motif arrangements systematically 130,131 in a high-throughput manner.”
- Direct measurement of DNA affinity landscapes on a high-throughput sequencing instrument (2011, positive): “This comparison suggested not only that low-affinity promoters are occupied only at higher Gcn4p concentrations, as expected from standard biophysical model”