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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
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Regulatory sharing between estrogen receptor α bound enhancers
Julia B Carleton1,2, Matthew Ginley-Hidinger1,3, Kristofer C Berrett1,2
1Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Nucleic Acids Research
|June 2, 2020
Summary
Multiple estrogen-responsive enhancers cooperate to regulate gene expression. A full estrogen response element (ERE) is crucial for estrogen receptor (ER) binding, while chromatin accessibility facilitates this process for synergistic gene regulation.
Area of Science:
- Genomics
- Molecular Biology
- Epigenetics
Background:
- The human genome has more gene enhancers than promoters, indicating complex gene regulation.
- Estrogen-responsive enhancers show synergistic effects on gene expression.
- The molecular mechanisms of enhancer cooperativity remain unclear.
Purpose of the Study:
- To investigate the molecular basis of cooperativity between neighboring estrogen-responsive enhancers.
- To understand how estrogen receptor (ER) binding and chromatin environment influence enhancer function.
Main Methods:
- Generated genetic deletions of four ER-bound enhancers regulating two genes.
- Utilized genome engineering to swap genomic sequences between enhancers.
- Assessed ER binding, histone acetylation, and chromatin accessibility.
Main Results:
- Enhancers with full estrogen response element (ERE) motifs dictated ER binding at adjacent sites.
- Enhancers with pre-existing histone acetylation conferred a permissive chromatin state.
- Two enhancers with half EREs could not compensate for a missing full ERE.
- Two enhancers with full EREs resulted in a greater transcriptional response than the wild-type locus.
- Genomic location of a full ERE significantly impacts enhancer activity.
Conclusions:
- A full ERE is essential for estrogen receptor recruitment.
- A permissive chromatin environment is also necessary for estrogen-driven gene regulation.
- Enhancer cooperativity involves a balance between specific DNA motifs and chromatin accessibility.
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