Histone modifications directly modulate transcription factor binding to nucleosomes

Transcription factors (TFs) that can recognize specific DNA sequences within nucleosomes play key roles in regulating cell fate transitions, but what regulates their condition-dependent binding to nucleosomes remains poorly understood. Here, we determined the direct effects of H3K27ac, H3K27me3 and H3K9me3 on binding by 7 human TFs to a highly diverse library of nucleosomes. We found that these marks influence the preference of FOXA1 and PAX7 to bind as monomers versus dimers to nucleosomes. Furthermore, H3K27ac impairs TF binding at internal regions of nucleosomes, enhancing end-binding preferences, for most of the assayed TFs. Our results suggest that histone marks represent an additional layer of cis-regulatory encoding that directly regulates TF interactions with nucleosomal binding sites.