Target Gene Repression Based on Dismissal of Polymerase II from Estrogen Receptor Trans-bound Enhancers Is Associated With Clinical Outcome in Human Breast Cancer [ChIP-seq]

We find that 17-β-estradiol (E2)-bound estrogen receptor α (ERα) is bound in trans to a cohort of FOXA1-dependent, constitutively activate enhancers, inactivating these enhancers by decommissioning/removing enhancer Polymerase II (Pol II), despite recruitment of coactivators. This is based on the surprising recruitment by the ERα DNA binding domain of the histone demethylase, KDM2A, which, functioning independently of its demethylase function. KDM2A mediates recruitment of NEDD4 complexes that ubiquitinate and dismisses Pol II from these "repressive" enhancers, resulting in the E2 down-regulated transcriptional program. Trans-bound estrogen receptor α (ERα) to the E2 repressed enhancers are proved by ERα pbox mutated ChIP-seq. ERα DNA binding domain interacts with histone demethylase, KDM2A, which mediates recruitment of NEDD4 complexes that dismisses Pol II from these "repressive" enhancers, resulting in the E2 down-regulated transcriptional program shown by GRO-seq and Pol II ChIP-seq. Overall, our data suggest that KDM2A plays central roles in a nuclear receptor-induced transcriptional repression program.