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Antiestrogen can establish nonproductive receptor complexes and alter chromatin structure at target enhancers
T A Pham1, J F Elliston, Z Nawaz
1Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
We describe in this report experiments in vivo that demonstrate that antiestrogens promote DNA binding of the estrogen receptor without efficiently inducing transcription. When the receptor is modified to carry a foreign unregulated transactivation domain, transcription can be induced efficiently by both estrogen and antiestrogens. Under apparent saturation conditions, antihormone-receptor complexes binding to responsive enhancer elements elicit only a low level of transcription. In addition, we show that both estrogen and an antiestrogen, nafoxidine, effect very similar alterations in chromatin structure at a responsive promoter. These results indicate that in vivo steroid receptor action can be regulated subsequent to the DNA binding step, by regulating interactions with the target transcriptional machinery. In this regard, antihormones can function by establishing receptor-DNA complexes that are transcriptionally nonproductive.
Insights
Antiestrogens bind the estrogen receptor to DNA but do not trigger transcription efficiently. This suggests that antihormones create nonproductive receptor-DNA complexes, regulating gene expression after DNA binding.
Area of Science:
- Molecular biology
- Endocrinology
- Genetics
Background:
- Estrogen receptor (ER) plays a crucial role in gene regulation.
- Antiestrogens are used in hormone-dependent diseases but their precise mechanism of action is debated.
- Understanding ER-mediated transcription is key to developing targeted therapies.
Purpose of the Study:
- To investigate the in vivo mechanism by which antiestrogens affect estrogen receptor (ER) transcriptional activity.
- To determine if ER DNA binding is sufficient for transcriptional induction by antiestrogens.
- To explore the role of transactivation domains and chromatin remodeling in antiestrogen action.
Main Methods:
- In vivo experiments assessing DNA binding and transcriptional activity of the estrogen receptor.
- Utilizing modified receptors with foreign transactivation domains.
- Chromatin structure analysis at responsive promoters using an antiestrogen (nafoxidine) and estrogen.
Main Results:
- Antiestrogens promote estrogen receptor (ER) DNA binding in vivo without efficient transcription induction.
- A modified ER with an unregulated transactivation domain shows efficient transcription with both estrogen and antiestrogens.
- Antihormone-ER complexes induce low-level transcription even at saturation.
- Estrogen and nafoxidine induce similar chromatin structure alterations at promoters.
Conclusions:
- Steroid receptor action in vivo is regulated post-DNA binding through interactions with transcriptional machinery.
- Antihormones function by forming transcriptionally nonproductive receptor-DNA complexes.
- This mechanism offers insights into targeted therapies for hormone-responsive conditions.