Transcriptional complexes engaged by apo-estrogen receptor-α isoforms have divergent outcomes

Abstract

Unliganded (apo-) estrogen receptor α (ERα, NR3A1) is classically considered as transcriptionally unproductive. Reassessing this paradigm demonstrated that apo-human ERα (ERα66) and its N-terminally truncated isoform (ERα46) are both predominantly nuclear transcription factors that cycle on the endogenous estrogen-responsive pS2 gene promoter in vivo. Importantly, isoform-specific consequences occur in terms of poising the promoter for transcription, as evaluated by determining (i) the engagement of several cofactors and the resulting nucleosomal organization; and (ii) the CpG methylation state of the pS2 promoter. Although transcriptionally unproductive, cycling of apo-ERα66 prepares the promoter to respond to ligand, through sequentially targeting chromatin remodeling complexes and general transcription factors. Additionally, apo-ERα46 recruits corepressors, following engagement of cofactors identical to those recruited by apo-ERα66. Together, these data describe differential activities of ERα isoforms: Furthermore, they depict the maintenance of a promoter in a repressed state as a cyclical process that is intrinsically dependent on initial poising of the promoter.