Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.

Area of Science:

• Molecular Biology
• Genomics
• Bioinformatics

Background:

• The impact of transcription factor dimerization on DNA-binding specificity remains largely unknown.
• Understanding these interactions is crucial for deciphering gene regulation.

Purpose of the Study:

• To investigate how dimerization influences the DNA-binding specificities of human bZIP transcription factors.
• To create a comprehensive map of bZIP-DNA interactions.

Main Methods:

• Examined DNA-binding specificities of 270 human bZIP pairs based on dimerization properties.
• Utilized Electrophoretic Mobility Shift Assay-Förster Resonance Energy Transfer (EMSA-FRET) for biochemical validation.
• Employed Chromatin Immunoprecipitation sequencing (ChIP-seq) for in vivo validation.

Main Results:

• Mapped DNA interactomes for 80 heterodimers and 22 homodimers.
• Discovered that 72% of heterodimer motifs matched conjoined half-sites, while 12% and 16% showed variable or emergent sites, respectively.
• Identified distinct binding preferences for ATF3 based on its dimerization partners.

Conclusions:

• Transcription factor dimerization profoundly shapes DNA-binding specificity, leading to novel and emergent binding sites.
• The genome-wide binding of factors like ATF3 is best understood by considering multiple dimeric forms.
• The study predicted bZIP binding to 156 disease-associated SNPs, significantly expanding known regulatory associations.