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A chromatin-mediated mechanism for specification of conditional transcription factor targets

Nature Genetics volume 38, pages 1446–1451 (2006)Cite this article

Abstract

Organisms respond to changes in their environment, and many such responses are initiated at the level of gene transcription. Here, we provide evidence for a previously undiscovered mechanism for directing transcriptional regulators to new binding targets in response to an environmental change. We show that repressor-activator protein 1 (Rap1), a master regulator of yeast metabolism, binds to an expanded target set after glucose depletion despite decreasing protein levels and no evidence of posttranslational modification. Computational analysis predicts that proteins capable of recruiting the chromatin regulator Tup1 act to restrict the binding distribution of Rap1 in the presence of glucose. Deletion of the gene(s) encoding Tup1, recruiters of Tup1 or chromatin regulators recruited by Tup1 cause Rap1 to bind specifically and inappropriately to low-glucose targets. These data, combined with whole-genome measurements of nucleosome occupancy and Tup1 distribution, provide evidence for a mechanism of dynamic target specification that coordinates the genome-wide distribution of intermediate-affinity DNA sequence motifs with chromatin-mediated regulation of accessibility to those sites.

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Figure 1: Rap1 binds to new targets in the absence of glucose.
Figure 2: In the absence of Tup1 or proteins that recruit Tup1, Rap1 binds specifically and inappropriately to low-glucose targets.
Figure 3: Tup1 restricts Rap1 binding through chromatin-modifying cofactors.
Figure 4: Low-glucose Rap1 targets contain Sko1, Sut1 or Mig1 binding sites and a weak Rap1 consensus motif.
Figure 5: Loss of nucleosomes allows Rap1 to bind to intermediate-affinity targets.
Figure 6: A 'nucleosome hair-trigger' model for condition-dependent transcription factor binding through coordinated interplay between local chromatin structure and DNA-binding affinity.

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Acknowledgements

We thank A.D. Johnson (Department of Microbiology and Immunology, University of California, San Francisco) for providing a strain. This work was supported by US National Institutes of Health grant HG002989 to M.J.B. and GM072518 to J.D.L.

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Authors and Affiliations

  1. Department of Biology and the Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Michael J Buck & Jason D Lieb

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  1. Michael J Buck
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  2. Jason D Lieb
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Contributions

This study was designed by M.J.B. and J.D.L. M.J.B conducted the experiments and data analysis. M.J.B. 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 Fig. 1

Rap1 protein and mRNA levels decrease as glucose is depleted. (PDF 462 kb)

Supplementary Fig. 2

Confirmation of ChIP-chip results by PCR. (PDF 1488 kb)

Supplementary Fig. 3

Confirmation of ChIP-chip results at the SGA1 locus. (PDF 924 kb)

Supplementary Fig. 4

Computational screens predict the involvement of Tup1-Ssn6 proteins in blocking Rap1 binding. (PDF 290 kb)

Supplementary Fig. 5

Rap1 binding and glycolysis. (PDF 372 kb)

Supplementary Table 1

ChIP-chip experiments. (PDF 53 kb)

Supplementary Table 2

Rap1 binding targets. (XLS 71 kb)

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Buck, M., Lieb, J. A chromatin-mediated mechanism for specification of conditional transcription factor targets. Nat Genet 38, 1446–1451 (2006). https://doi.org/10.1038/ng1917

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