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.DOI: http://dx.doi.org/10.7554/eLife.19272.001

The Epstein-Barr Virus B-ZIP Protein Zta Recognizes Specific DNA Sequences Containing 5-Methylcytosine and 5-Hydroxymethylcytosine

“…B-ZIP domains bind DNA as homo- or hetero-dimers, with each monomer interacting with one half of the DNA sequence motif 11–13 . A recent structural comparison between the cJun homodimer binding meTRE and Zta homodimers binding meZRE2 highlight several amino acids important for B-ZIP recognition of methylated DNA 14 .…”

Nach is a novel ancestral subfamily ofthe CNC-bZIP transcription factors selected during evolution from the marine bacteria to human

“…Conversely, the failure of these bZIP factors to control the activity of given genes ultimately results in the pathogenesis of cancer, diabetes or a wide array of other diseases. Thus, the complex regulatory network of bZIP subfamily through interacting with their dimeric partners and/or other different members to control transcriptional expression of many genes is ensured to act as a key means for diverse cellular responses to complex and in constant environments, as described by authors referenced (57). Overall, diverse interactions of distinct bZIP factors with different partners elicit different regulatory effects on target genes.…”

Context-dependent gene regulation by transcription factor complexes

“…However, since DBDs were used rather than full-length proteins, the contacts observed in these structures may not capture all relevant contributions to complex stability. To determine whether the sequence of the DNA spacer might contribute to the thermodynamic stability of the complex, we computed oligomer enrichment over the first four nucleotide positions 150 downstream of the fixed Hth site in Lib-Hth-R, retaining only those probes that matched the 12bp PSAM for Exd-Hox over positions [5][6][7][8][9][10][11][12][13][14][15][16]. A preference for AT-rich sequences observed in the most highly enriched spacers ( Fig.…”

“…The four separate, raw fastq-files (from the four lanes of the sequencing run) were first collapsed into one file and subsequently aligned (bowtie2) (12) to the D. melanogaster genome version dm6 (2014, GenBank accession: GCA_000001215.4). Aligned sam files were next converted into bam files, sorted and cleared from duplicate reads 1005 using the samtools functions view, sort and rmdup (13)(14)(15). The sorted, unique bam files were indexed and converted into bigwig files using the bamCoverage function in the Deeptools suite with parameters -bs 1 -e 125 (16).…”

“…There are several possible explanations for this: For one, low-affinity binding sites, which generally do not harbor a motif match, can be bound and functional in vivo (9,10). Second, a TF may bind its genomic target sites cooperatively with other TFs (11)(12)(13)(14)(15) or with nucleosomes (16). Finally, indirect pull-down at highly accessible sites (17) or experimental artifacts (18) may also contribute.…”