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Genome-wide protein–DNA binding dynamics suggest a molecular clutch for transcription factor function


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 rapidly1,2,3,4. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor occupancy5, 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 (R2 = 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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Figure 1: Development of transcription factor competition ChIP yeast strains.
Figure 2: Rap1-bound sites exhibit distinct replacement dynamics.
Figure 3: RNA polymerase II recruitment, mRNA production, and histone acetyltransferase recruitment is associated with long Rap1 residence.
Figure 4: Evidence for competition between Rap1 and nucleosomes.

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Primary accessions

Gene Expression Omnibus

Data deposits

Data has been deposited in the Gene Expression Omnibus under accession numbers GSE32351 (ChIP-on-chip data), GPL14612 (ChIP platform), GSM677030–GSM677033 (RNA expression array data) and GPL4414 (expression platform).


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We thank T. Kaplan and O. Rando for help with their turnover model, T. Palpant and S. Adar for help with time course experiments, and A. Leonardo Iniguez and H. Rosenbaum of Roche Nimblegen for pre-release custom HD4 12-plex microarrays. This work was supported by the US National Institutes of Health (NIH) Grant R01-GM072518 (to J.D.L.), and the intramural program of the NIH, National Cancer Institute, Center for Cancer Research (to J.G.M. and F.M.). F.M. was also supported in part by the Region Ile-de-France in the framework of C’Nano IdF, the nanoscience competence center of Paris Region.

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Authors and Affiliations



C.R.L., S.E.H. and J.D.L. designed the study. C.R.L. and S.E.H. performed the experiments. F.M. developed and implemented the binding dynamics model. C.R.L., F.M., J.G.M. and J.D.L. performed data analysis. C.R.L., F.M., J.G.M. and J.D.L. wrote the paper.

Corresponding author

Correspondence to Jason D. Lieb.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Figures 1-12 and Supplementary References. (PDF 1885 kb)

Supplementary Table

This file contains Supplementary Table 1 which shows residence times and genomic coordinates for 439 Rap1 targets. (XLS 98 kb)

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Lickwar, C., Mueller, F., Hanlon, S. et al. Genome-wide protein–DNA binding dynamics suggest a molecular clutch for transcription factor function. Nature 484, 251–255 (2012).

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