Transcriptional complexes engaged by apo-estrogen receptor-alpha isoforms have divergent outcomes.
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.
Métivier
Raphaël
R
European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. Raphael.metivier@univ-rennes1.fr
Penot
Graziella
G
Carmouche
Richard P
RP
Hübner
Michael R
MR
Reid
George
G
Denger
Stefanie
S
Manu
Dominique
D
Brand
Heike
H
Kos
Martin
M
Benes
Vladimir
V
Gannon
Frank
F
D001059:Apoproteins / Q000235:genetics* / Q000378:metabolism; D001683:Biological Clocks; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D053766:Presenilin-2; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D001059:Apoproteins; D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006133:Growth Substances; D008024:Ligands; D008565:Membrane Proteins; D009707:Nucleosomes; C508861:PSEN2 protein, human; D053766:Presenilin-2; D020033:Protein Isoforms; D014157:Transcription Factors