Phase Separation of FOXA1 Unpacks the Condensed Chromatin to Function as a Pioneer Factor
Eukaryotic DNA is packaged into chromatin in the nucleus, which restricts the binding of transcription factors (TFs) to the target DNA sites. FOXA1 functions as a pioneer TF to bind condensed chromatin and initiate the opening of local chromatin for gene expression. However, the principles of how FOXA1 recruits to and unpacks the condensed chromatin remain elusive. Here, we revealed that FOXA1 intrinsically undergoes phase separation through its N- and C-terminal intrinsically disordered regions (IDRs). Notably, the property that allows FOXA1 to phase separate enables FOXA1 to dissolve the condensed chromatin. In addition, the DNA-binding capacity of FOXA1 contributes to its phase-separation property. Further genome-wide investigation showed that FOXA1 is recruited to and unpacks the condensed chromatin by its IDRs to regulate the proliferation and migration of breast cancer cells. This work provides a principle of how pioneer TFs function to initiate competent chromatin states by phase separation.