Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering

FOXA1 functions in epigenetic reprogramming and is described as a 'pioneer factor'. However, exactly how FOXA1 achieves these remarkable biological functions is not fully understood. Here we report that FOXA1 associates with DNA repair complexes and is required for genomic targeting of DNA polymerase beta (POLB) in human cells. Genome-wide DNA methylomes demonstrate that the FOXA1 DNA repair complex is functionally linked to DNA demethylation in a lineage-specific fashion. Depletion of FOXA1 results in localized reestablishment of methylation in a large portion of FOXA1-bound regions, and the regions with the most consistent hypermethylation exhibit the greatest loss of POLB and are represented by active promoters and enhancers. Consistently, overexpression of FOXA1 commits its binding sites to active DNA demethylation in a POLB-dependent manner. Finally, FOXA1-associated DNA demethylation is tightly coupled with estrogen receptor genomic targeting and estrogen responsiveness. Together, these results link FOXA1-associated DNA demethylation to transcriptional pioneering by FOXA1.