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Genome-wide protein–DNA binding dynamics suggest a molecular clutch for transcription factor function
Open accessAbstract
Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor occupancy, but give no indication of kinetics and are poor predictors of transcription factor function at a given locus. To measure transcription-factor-binding dynamics across the genome, we performed competition ChIP (refs 6, 7) with a sequence-specific Saccharomyces cerevisiae transcription factor, Rap1 (ref. 8). Rap1-binding dynamics and Rap1 occupancy were only weakly correlated (R(2) = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, whereas fast binding turnover, which we refer to as 'treadmilling', was linked to low transcriptional output. Thus, DNA-binding events that seem identical by conventional ChIP may have different underlying modes of interaction that lead to opposing functional outcomes. We propose that transcription factor binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated mainly by control of competition between transcription factors and nucleosomes. Our model predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice versa, to modulate transcription factor function.
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“Transcription factors undergo fast turnover at non-functional binding sites that can be fixated during ChIP protocol, thereby leading to false-positive hits,139”
From Census and evaluation of p53 target genes (2017) · cites this paper as [139]
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“Notably, the ChIP technique in general can produce false findings.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [139]
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Metadata
- Authors
- Lickwar, C. R., Mueller, F., Hanlon, S. E., McNally, J. G., & Lieb, J. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Centre National de la Recherche Scientifique (FR)
- National Institutes of Health (US)
- Corresponding author
- Lieb, Jason D.
- Venue
- Nature
- Published
- 2012-04-11
- Volume
- 484
- Issue
- 7393
- Pages
- 251-255
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3341663
- OpenAlex
- W2008226163
- Cited by
- 241
- References
- 41
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 15 · 2020: 13 · 2019: 11 · 2018: 13 · 2017: 19 · 2016: 18 · 2015: 25 · 2014: 31 · 2013: 38 · 2012: 13
- FWCI
- 13.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UNC Libraries
- Funders
- Centre de Compétences Nanosciences Ile-de-France
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM072518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Rap1, transcriptional activation, transcription factor occupancy, treadmilling, clutch mechanism, Saccharomyces cerevisiae, genome-wide binding
- MeSH terms
- Shelterin Complex, Base Sequence, Binding Sites, Binding, Competitive, DNA, Fungal, Models, Biological, Nucleosomes, Protein Binding, RNA Polymerase II, RNA, Messenger, Saccharomyces cerevisiae, Time Factors, Transcription Factors, Gene Expression Regulation, Fungal, Genome, Fungal, Saccharomyces cerevisiae Proteins, Telomere-Binding Proteins, Chromatin Immunoprecipitation, Histone Acetyltransferases
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