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

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 endo...

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Bibliographic Details
Published in:The EMBO journal 2004-09, Vol.23 (18), p.3653-3666
Main Authors: Métivier, Raphaël, Penot, Graziella, Carmouche, Richard P, Hübner, Michael R, Reid, George, Denger, Stefanie, Manu, Dominique, Brand, Heike, Koš, Martin, Benes, Vladimir, Gannon, Frank
Format: Article
Language:English
Subjects:
Apoproteins - genetics
Apoproteins - metabolism
Biological Clocks
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
ChIP
Chromatin - metabolism
Chromatin Immunoprecipitation
CpG Islands
DNA Methylation
Epigenesis, Genetic - genetics
estrogen receptor
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogens - metabolism
Gene Expression Regulation, Neoplastic
Growth Substances - metabolism
Humans
Ligands
Membrane Proteins - genetics
Membrane Proteins - metabolism
methylation
Nucleosomes - metabolism
Presenilin-2
Promoter Regions, Genetic - genetics
Protein Isoforms
transcription
Transcription Factors - metabolism
Transcription, Genetic
Transcriptional Activation
unliganded
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Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600377