A Novel Approach to Assay DNA Methylation in Prostate Cancer

Forkhead box A1 (FOXA1) is an FKHD family pro-tein that plays pioneering roles in lineage-specificenhancer activation and gene transcription. Throughgenome-wide location analyses, here we show thatFOXA1 expression and occupancy are, in turn, re-quired for the maintenance of these epigeneticsignatures, namely DNA hypomethylation and his-tone 3 lysine 4 methylation. Mechanistically, this in-volves TET1, a 5-methylcytosine dioxygenase. Wefound that FOXA1 induces TET1 expression via di-rect binding to its cis-regulatory elements. Further,FOXA1 physically interacts with the TET1 proteinthrough its CXXC domain. TET1 thus co-occupiesFOXA1-dependent enhancers and mediates localDNA demethylation and concomitant histone 3 ly-sine 4 methylation, further potentiating FOXA1 re-cruitment. Consequently, FOXA1 binding events aremarkedly reduced following TET1 depletion. To-gether, our results suggest that FOXA1 is not onlyable to recognize but also remodel the epigenetic sig-natures at lineage-specific enhancers, which is me-diated, at least in part, by a feed-forward regulatoryloop between FOXA1 and TET1.