ABCG2 regulatory single-nucleotide polymorphisms alter in vivo enhancer activity and expression
| Autor: | Deanna L. Kroetz, Robin P. Smith, Mee J. Kim, Nadav Ahituv, Rachel J. Eclov, Aparna Chhibber |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Messenger Subfamily G Kidney polymorphism Mice Gene expression Genes Regulator 2.1 Biological and endogenous factors ATP Binding Cassette Transporter Subfamily G Member 2 transcriptional regulation Pharmacology & Pharmacy General Pharmacology Toxicology and Pharmaceutics Nuclear protein Genetics (clinical) Cancer Nuclear Proteins Single Nucleotide Pharmacology and Pharmaceutical Sciences Hep G2 Cells Neoplasm Proteins Enhancer Elements Genetic Liver Regulatory sequence breast cancer resistance protein embryonic structures Molecular Medicine Protein Binding Member 2 Enhancer Elements ATP Binding Cassette Transporter ABCG2 Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Article 03 medical and health sciences Genetic In vivo Breast Cancer ATP-binding cassette transporter Genetics Animals Humans RNA Messenger Enhancer Molecular Biology Gene Sub-Family G pharmacogenomics Regulator Human Genome Kidney metabolism Molecular biology 030104 developmental biology HEK293 Cells Genes RNA sense organs enhancer Digestive Diseases |
| Zdroj: | Pharmacogenetics and genomics, vol 27, iss 12 |
| ISSN: | 1744-6880 |
| Popis: | Author(s): Eclov, Rachel J; Kim, Mee J; Chhibber, Aparna; Smith, Robin P; Ahituv, Nadav; Kroetz, Deanna L | Abstract: ObjectivesThe expression and activity of the breast cancer resistance protein (ABCG2) contributes toward the pharmacokinetics of endogenous and xenobiotic substrates. The effect of genetic variation on the activity of cis-regulatory elements and nuclear response elements in the ABCG2 locus and their contribution toward ABCG2 expression have not been investigated systematically. In this study, the effect of genetic variation on the in vitro and in vivo enhancer activity of six previously identified liver enhancers in the ABCG2 locus was examined.MethodsReference and variant liver enhancers were tested for their ability to alter luciferase activity in vitro in HepG2 and HEK293T cell lines and in vivo using a hydrodynamic tail vein assay. Positive in vivo single-nucleotide polymorphisms (SNPs) were tested for association with gene expression and for altered protein binding in electrophoretic mobility shift assays.ResultsMultiple SNPs were found to alter enhancer activity in vitro. Four of these variants (rs9999111, rs12508471, ABCG2RE1*2, and rs149713212) decreased and one (rs2725263) increased enhancer activity in vivo. In addition, rs9999111 and rs12508471 were associated with ABCG2 expression in lymphoblastoid cell lines, lymphocytes, and T cells, and showed increased HepG2 nuclear protein binding.ConclusionThis study identifies SNPs within regulatory regions of the ABCG2 locus that alter enhancer activity in vitro and in vivo. Several of these SNPs correlate with tissue-specific ABCG2 expression and alter DNA/protein binding. These SNPs could contribute toward reported tissue-specific variability in ABCG2 expression and may influence the correlation between ABCG2 expression and disease risk or the pharmacokinetics and pharmacodynamics of breast cancer resistance protein substrates. |
| Databáze: | OpenAIRE |
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