Sequence-specific transcription factors (TFs) regulate gene expression by binding to cis-regulatory elements in promoter and enhancer DNA. While studies of TF-DNA binding have focused on TFs' intrinsic preferences for primary nucleotide sequence motifs, recent studies have elucidated additional layers of complexity that modulate TF-DNA binding. In this review, we discuss technological developments for identifying TF binding preferences and highlight recent discoveries that elaborate how TF interactions, local DNA structure, and genomic features influence TF-DNA binding. We highlight novel approaches for characterizing functional binding site motifs that promise to inform our understanding of how TF binding controls gene expression and ultimately contributes to phenotype.
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