Nucleation of DNA Repair Factors by FOXA1 Links DNA Demethylation and Transcriptional Pioneering

ABSTRACT: We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.

OTHER RELATED OMICS DATASETS IN: PRJNA320049

INSTRUMENT(S): LTQ

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Yu Zhang  

LAB HEAD: Yongfeng Shang

PROVIDER: PXD004271 | Pride | 2016-06-08

REPOSITORIES: Pride