Genomic actions of estrogen receptor α: what are the targets and how are they regulated?
- Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, PO Box 9101, HB Nijmegen, The
Netherlands Departments of
1Chemical Endocrinology
2Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- (Correspondence should be addressed to H G Stunnenberg; Email: h.stunnenberg{at}ncmls.ru.nl)
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Figure 2
Overview of ERα-mediated regulation of transcription. Activation of genes by an unliganded receptor is prevented due to methylation of histone tails by H3K9-specific histone methyl transferases. Ligand, e.g. estradiol (E2) or the SERM tamoxifen, diffuses through the cellular membrane and binds cytoplasmic ERα. Upon ligand binding ERα disassociates from chaperone proteins such as hsp90, translocates to the nucleus and dimerizes. The ERα binds chromatin and in a subset of genes recruits the histone demethylase LSD1. LSD1 removes the methyl mark that prevents gene activation by the unliganded receptor and also plays a role in the interaction of distal enhancer regions via looping. At upregulated genes, cofactors such as AIB1 (p160 family) are recruited and a complex containing histone acetyl transferase activity is assembled. The N-terminal histone tails are acetylated, resulting in an open chromatin conformation. In addition, cofactors with nucleosome remodeling activity (BRG1/BRM) are recruited. Finally, RNA polymerase II and the general transcription machinery assemble at the promoter and the gene is transcribed. At repressed genes, either E2-repressed genes or genes repressed upon tamoxifen treatment, the corepressors NCoR or SMRT are recruited and a histone deacetylase complex is assembled. Acetyl groups are removed from histone tails and the chromatin is in a closed conformation, which is not permissive for transcription to occur.
- © 2009 Society for Endocrinology
