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  • The EMBO Journal (2004) 23, 3653 - 3666
  • doi:10.1038/sj.emboj.7600377

Published online: 2 September 2004

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

Raphaël Métivier1,2, Graziella Penot1,2, Richard P Carmouche1, Michael R Hübner1, George Reid1, Stefanie Denger1, Dominique Manu1, Heike Brand1, Martin Kos caron1,a, Vladimir Benes1 and Frank Gannon1

  1. European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
  2. Present address: Equipe d'Endocrinologie Moléculaire de la Reproduction (EMR), UMR CNRS 6026, Université de Rennes I, 35042 Rennes Cedex, France

Correspondence to:

Raphaël Métivier, Equipe d'Endocrinologie Moléculaire de la Reproduction (EMR), UMR CNRS 6026 (ICM), Université de Rennes I, Campus de Beaulieu, Batiment 13, Pièce 037, 35042 Rennes Cedex, France. Tel.: +33 2 23 23 51 42; Fax: +33 2 23 23 67 94; E-mail: Raphael.metivier@univ-rennes1.fr

aPresent address: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Mayfield Road, Edinburgh EH9 3JR, UK

Received 4 May 2004; Accepted 29 July 2004

Unliganded (apo-) estrogen receptor alpha (ERalpha, NR3A1) is classically considered as transcriptionally unproductive. Reassessing this paradigm demonstrated that apo-human ERalpha (ERalpha66) and its N-terminally truncated isoform (ERalpha46) 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-ERalpha66 prepares the promoter to respond to ligand, through sequentially targeting chromatin remodeling complexes and general transcription factors. Additionally, apo-ERalpha46 recruits corepressors, following engagement of cofactors identical to those recruited by apo-ERalpha66. Together, these data describe differential activities of ERalpha 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.

  • Keywords:

    • ChIP,
    • estrogen receptor,
    • methylation,
    • transcription,
    • unliganded