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Transcriptional complexes engaged by apo‐estrogen receptor‐α isoforms have divergent outcomes
Author(s) -
Métivier Raphaël,
Penot Graziella,
Carmouche Richard P,
Hübner Michael R,
Reid George,
Denger Stefanie,
Manu Dominique,
Brand Heike,
Koš Martin,
Benes Vladimir,
Gan Frank
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600377
Subject(s) - biology , gene isoform , estrogen receptor , estrogen , genetics , microbiology and biotechnology , gene , breast cancer , cancer
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.