Jolma, A. et al. Nature 527, 384–388 (2015).

The interplay between transcription factors (TFs) and DNA is still subject to intense investigation. Binding motifs for many TFs are known, as is the fact that TFs can bind as pairs to multiple motifs. What remains unclear is the prevalence of such pairings and whether DNA sequences determine binding. Jolma et al. systematically addressed this question with a strategy of selection and enrichment. They labeled TFs with different tags and enriched for DNA sequences bound by TF pairs in consecutive rounds of pulldowns. Most of the enriched TF pairs showed DNA-mediated cooperative binding and recognized composite motifs different from those of the individual TFs. The researchers estimate that ∼25,000 TF pairs—a much larger number than previously anticipated—contribute to DNA regulatory interactions in cells.