Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal DNA to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially access solvent-exposed motifs near the entry/exit sites, and frequently interact with histones. The extent of TF–histone interactions, in turn, depends on the motif location on the nucleosome, the type of DNA-binding fold, and adjacent domains present. TF–histone interactions can phase TF motifs relative to nucleosomes, and we discuss how these complex and surprisingly diverse interactions between nucleosomes and TFs contribute to function.