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Elife. 2017 Feb 10;6. pii: e19272. doi: 10.7554/eLife.19272.

Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.

Author information

1
Department of Biochemistry, University of Wisconsin-Madison, Madison, United States.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
3
Department of Electrical and Computer Engineering, University of Wisconsin-Madison, Madison, Unites States.
4
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States.
5
The Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, United States.

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.

KEYWORDS:

SELEX; computational biology; evolutionary biology; gene regulation; genetic variants; genomics; human; protein-DNA interactions; sequence specificity landscapes; systems biology; transcription factors

PMID:
28186491
PMCID:
PMC5349851
DOI:
10.7554/eLife.19272
[Indexed for MEDLINE]
Free PMC Article

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