Chromatin information content landscapes inform transcription factor and DNA interactions

The dynamic interactions between transcription factors (TFs) and chromatin are a fundamental component of genome regulation. Their biological principles, however, remain incompletely understood. Here, we develop information theory algorithms to measure signatures of TF-chromatin interactions encoded in patterns of the accessible genome, which we call chromatin information enrichment. We calculate chromatin information enrichment for hundreds of TF motifs across human tissues and find significant associations with TF-DNA residence times and specific DNA binding domains. Most TF motifs have low chromatin information enrichment and have lower performance with footprinting methods, but the subset of TF motifs associated with high chromatin information enrichment are more highly enriched to overlap genetic variants linked to gene expression and associate with increased chromatin accessibility and nucleosome phasing. Our results provide insights into how TF-chromatin interactions shape the regulatory landscape in the cell.