1. Computational and Systems Biology
  2. Chromosomes and Gene Expression
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Combinatorial bZIP dimers define complex DNA-binding specificity landscapes

  1. Jose A Rodriguez-Martinez
  2. Aaron W Reinke
  3. Devesh Bhimsaria
  4. Amy E Keating
  5. Aseem Z Ansari  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. Massachusetts Institute of Technology, United States
Research Article
  • Cited 17
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Cite this article as: eLife 2017;6:e19272 doi: 10.7554/eLife.19272

Abstract

How transcription factor dimerization impacts DNA binding specificity is poorly understood. Guided by protein dimerization properties, we examined DNA binding specificities of 270 human bZIP pairs. DNA interactomes of 80 heterodimers and 22 homodimers revealed that 72% of heterodimer motifs correspond to conjoined half-sites preferred by partnering monomers. Remarkably, the remaining motifs are composed of variably-spaced half-sites (12%) or 'emergent' sites (16%) that cannot be readily inferred from half-site preferences of partnering monomers. These binding sites were biochemically validated by EMSA-FRET analysis and validated in vivo by ChIP-seq data from human cell lines. Focusing on ATF3, we observed distinct cognate site preferences conferred by different bZIP partners, and demonstrated that genome-wide binding of ATF3 is best explained by considering many dimers in which it participates. Importantly, our compendium of bZIP-DNA interactomes predicted bZIP binding to 156 disease associated SNPs, of which only 20 were previously annotated with known bZIP motifs.

Article and author information

Author details

  1. Jose A Rodriguez-Martinez

    Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1191-2887
  2. Aaron W Reinke

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7612-5342
  3. Devesh Bhimsaria

    Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amy E Keating

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Aseem Z Ansari

    Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
    For correspondence
    azansari@wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1432-4498

Funding

National Institutes of Health (R01GM096466)

  • Amy E Keating

W. M. Keck Foundation

  • Aseem Z Ansari

National Institutes of Health (U01HL099773)

  • Aseem Z Ansari

National Institutes of Health (R01CA133508)

  • Aseem Z Ansari

National Institutes of Health (T32HG002760)

  • Jose A Rodriguez-Martinez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: June 30, 2016
  2. Accepted: February 6, 2017
  3. Accepted Manuscript published: February 10, 2017 (version 1)
  4. Version of Record published: March 14, 2017 (version 2)

Copyright

© 2017, Rodriguez-Martinez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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