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Progesterone-dependent deoxyribonucleic acid looping between RUSH/SMARCA3 and Egr-1 mediates repression by c-Rel
Aveline Hewetson1, Beverly S Chilton
1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Texas 79430, USA.
Molecular Endocrinology (Baltimore, Md.)
|January 5, 2008
Summary
Steroid hormones regulate RUSH/SMARCA3 alternative splicing, producing alpha and beta isoforms. Progesterone-induced transcription involves RUSH-1alpha autoregulation and DNA looping with Egr-1/c-Rel for repression.
Area of Science:
- Molecular Biology
- Gene Regulation
- Steroid Hormone Action
Background:
- Steroids are crucial regulators of gene expression.
- Alternative splicing generates protein diversity.
- RUSH/SMARCA3 gene expression is influenced by hormonal cues.
Purpose of the Study:
- To elucidate the mechanism of steroid-regulated alternative splicing of RUSH/SMARCA3.
- To identify the transcription factors and regulatory elements involved in RUSH/SMARCA3 gene expression.
- To understand the role of RUSH isoforms in transcriptional regulation.
Main Methods:
- Analysis of RUSH/SMARCA3 promoter and 5'-untranslated region.
- Hormone treatment and isoform-specific binding studies.
- Chromatin immunoprecipitation (ChIP) and Chromosome Conformation Capture (3C) assays.
- Fluorescent microscopy and glutathione S-transferase (GST) pull-down assays.
- Transient transfection assays.
Main Results:
- Steroids induce alternative splicing of RUSH/SMARCA3 into alpha (progesterone-dependent) and beta (estrogen-dependent) isoforms.
- Progesterone-induced transcription involves a bipartite promoter element and GC-rich sequences.
- RUSH-1alpha interacts with Egr-1 and c-Rel via DNA looping to repress transcription.
- RUSH-1beta binds in the absence of progesterone, preventing DNA looping and repression.
Conclusions:
- Steroid hormones fine-tune RUSH/SMARCA3 transcription through isoform-specific autoregulation.
- DNA looping mediated by RUSH-1alpha, Egr-1, and c-Rel is a key mechanism for progesterone-induced transcriptional repression.
- The hormonal milieu dictates RUSH isoform availability and subsequent transcriptional outcomes.
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