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In Vivo Hepatic Enhancer Elements in the Human ABCG2 Locus
Rachel J Eclov1, Mee J Kim1, Robin P Smith1
1Department of Bioengineering and Therapeutic Sciences (R.J.E., M.J.K., R.P.S., X.L., N.A., D.L.K.); and Institute for Human Genetics (M.J.K., R.P.S., N.A., D.L.K.), University of California, San Francisco, San Francisco, California.
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 19, 2016
Summary
Researchers identified regulatory DNA regions around the ABCG2 gene that control its expression. Some regions respond to environmental stimuli like drugs, impacting drug response variations.
Area of Science:
- Genomics
- Molecular Biology
- Pharmacogenomics
Background:
- ABCG2 (ATP-binding cassette transporter G2) is a membrane transporter involved in drug resistance.
- Understanding ABCG2 regulation is crucial for predicting drug response variability.
Purpose of the Study:
- To identify and characterize cis-regulatory elements controlling human ABCG2 gene expression.
- To investigate the influence of environmental stimuli on ABCG2 regulatory elements.
Main Methods:
- Computational analysis of the ABCG2 genomic region to identify potential cis-regulatory elements.
- In vitro luciferase reporter assays in human liver cells to test enhancer/suppressor activity.
- In vivo validation in mouse models and response assessment to 17β-estradiol and rifampin.
Main Results:
- Identified 30 potential cis-regulatory regions around ABCG2.
- Discovered nine regions with significant enhancer or suppressor activity in vitro.
- Confirmed five in vitro enhancers as functional in vivo liver enhancers.
- Two enhancers (ABCG2RE1, ABCG2RE9) showed responsiveness to 17β-estradiol or rifampin.
Conclusions:
- Genomic regions surrounding ABCG2 possess regulatory functions that modulate gene expression.
- Identified regulatory elements can respond to environmental stimuli, influencing ABCG2 expression.
- These findings provide a basis for understanding interindividual differences in ABCG2 expression and drug response.
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