Combinatorial bZIP dimers display complex DNA-binding specificity landscapes

Elife. 2017 Feb 10;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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin Immunoprecipitation
  • DNA / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Multimerization*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism*
  • Substrate Specificity
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*

Substances

  • ALYREF protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Transcription Factors
  • DNA