Figure 1.

The dual role of FOXA as a pioneer and settler transcription factor. FOXA can bind target DNA sequences around nucleosomes in condensed chromatin. The first step, FOXA scans the chromatin laterally (12) and uses short anchoring α-helix structures to identify DNA motifs (13). The second step, since the crystal structure of the DBD of FOXA is highly similar to the ligand histone, they both use a “winged helix” structure to bind to DNA along the long axis of DNA (10, 14). In some cases, FoxA can replace linker histones (15). Then, induction of nucleosome repositioning and recruitment of co-transcription factors such as hepatocyte nuclear factor 4α (HNF4α), followed by high chromatin accessibility and aggregation of methylated H3K4 (H3K4me1) and acetylated H3K27 (H3K27ac). The resulting permissive chromatin state promotes transcriptional initiation, as FOXA cooperates with HNF4α to activate liver-specific genes (16).