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

EMBO J. 2004 Sep 15;23(18):3653-66. doi: 10.1038/sj.emboj.7600377. Epub 2004 Sep 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoproteins / genetics*
  • Apoproteins / metabolism
  • Biological Clocks
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation
  • CpG Islands
  • DNA Methylation
  • Epigenesis, Genetic / genetics
  • 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
  • Nucleosomes / metabolism
  • Presenilin-2
  • Promoter Regions, Genetic / genetics*
  • Protein Isoforms
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Activation


  • Apoproteins
  • Chromatin
  • Estrogen Receptor alpha
  • Estrogens
  • Growth Substances
  • Ligands
  • Membrane Proteins
  • Nucleosomes
  • PSEN2 protein, human
  • Presenilin-2
  • Protein Isoforms
  • Transcription Factors