title: Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
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.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, United States.
authors.forename: José A
authors.identifier: 0000-0002-1191-2887
authors.initials: JA
authors.lastname: Rodríguez-Martínez
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Aaron W
authors.identifier: 0000-0001-7612-5342
authors.initials: AW
authors.lastname: Reinke
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, United States.|Department of Electrical and Computer Engineering, University of Wisconsin-Madison, Madison, Unites States.
authors.forename: Devesh
authors.initials: D
authors.lastname: Bhimsaria
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Keating
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, United States.|The Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, United States.
authors.forename: Aseem Z
authors.identifier: 0000-0003-1432-4498
authors.initials: AZ
authors.lastname: Ansari
mesh_terms: D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C105242:ALYREF protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA
keywords: SELEX; computational biology; evolutionary biology; gene regulation; genetic variants; genomics; human; protein-DNA interactions; sequence specificity landscapes; systems biology; transcription factors