| Summary: | A major question in transcription factor (TF) biology is why a TF binds to only a small fraction of motif eligible binding sites in the genome. Using the estrogen receptor‐α as a model system, we sought to explicitly define parameters that determine TF‐binding site selection. By examining 12 genetic and epigenetic parameters, we find that an energetically favorable estrogen response element (ERE) motif sequence, co‐occupancy by the TF FOXA1, the presence of the H3K4me1 mark and an open chromatin configuration in the pre‐ligand state provide specificity for ER binding. These factors can model estrogen‐induced ER binding with high accuracy (ROC‐AUC=0.95 and 0.88 using different genomic backgrounds). Moreover, when assessed in another estrogen‐responsive cell line, this model was highly predictive for ERα binding (ROC‐AUC=0.86). Variance in binding site selection between MCF‐7 and T47D resides in sites with suboptimal ERE motifs, but modulated by the chromatin configuration. These results suggest a definable interplay between sequence motifs and local chromatin in selecting TF binding.
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