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Cited by 304Gene Regulatory Network AnalysisGenomics and Chromatin DynamicsFungal and yeast genetics research

Analysis of combinatorial cis-regulation in synthetic and genomic promoters

Open access
Gertz, Jason, Siggia, Eric D., Cohen, Barak A.·2009·Nature
DOI 10.1038/nature07521PMC PMC2677908
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Abstract

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.

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  • Measuring enhancer activity of synthetic, systematically designed DNA sequences with TFBSs placed in an otherwise inert sequence context is an alternative way to study the cis-regulatory code.

    “An alternative way to study the cis-regulatory code is to measure the enhancer activity of synthetic, systematically designed DNA sequences, where TF binding sites (TFBSs) are placed in an otherwise inert sequence context.27,30,31,32,33,34”

    From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [31]

    The paper describes synthetic libraries of transcription-factor binding sites placed upstream of a basal promoter, with activity measured by YFP expression (Abstract; page unavailable). It studies promoter activity rather than explicitly measuring enhancer activity. Moreover, a spacer designed to lack known regulatory elements appeared to recruit RNA polymerase, so the copy does not establish that the surrounding sequence was inert. (LLM, conf=0.88)

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Research works printed but not linked: 21

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Cited by

Sorted by citations

Authors
Gertz, J., Siggia, E. D., & Cohen, B. A.
Affiliations
  • Washington University in St. Louis (US)
  • Rockefeller University (US)
Corresponding author
Cohen, Barak A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2008-11-23
Volume
457
Issue
7226
Pages
215-218
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature07521
PMC
PMC2677908
OpenAlex
W2143855992
Cited by
304
References
1
Citations by year
2026: 5 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 14 · 2019: 11 · 2018: 15 · 2017: 14 · 2016: 18 · 2015: 27 · 2014: 17 · 2013: 34 · 2012: 28
FWCI
10.00
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
National Institute of General Medical Sciences (R01GM078222)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
transcription factor binding sites, synthetic promoters, promoter library, cooperativity, Saccharomyces cerevisiae, chromatin, protein-DNA interactions, protein-protein interaction, gene expression prediction
MeSH terms
Allosteric Site, DNA, DNA-Binding Proteins, Genes, Synthetic, Models, Genetic, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Saccharomyces cerevisiae, Thermodynamics, Transcription Factors, Down-Regulation, Gene Library, Gene Expression Regulation, Fungal, Genome, Fungal, Saccharomyces cerevisiae Proteins

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