In Vivo Hepatic Enhancer Elements in the Human ABCG2 Locus
| Autor: | Mee J. Kim, Rachel J. Eclov, Nadav Ahituv, Robin P. Smith, Xiaomin Liang, Deanna L. Kroetz |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Abcg2 Pharmaceutical Science Enhancer RNAs Antineoplastic Agents Biology Regulatory Sequences Nucleic Acid Transfection 03 medical and health sciences Mice In vivo Gene expression ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Cloning Molecular Enhancer Transcription factor Luciferases Renilla Pharmacology Estradiol HEK 293 cells Hep G2 Cells Articles HCT116 Cells Molecular biology 030104 developmental biology Enhancer Elements Genetic HEK293 Cells Liver Regulatory sequence Drug Resistance Neoplasm biology.protein Hepatocytes MCF-7 Cells Mitoxantrone Rifampin Protein Binding |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 45(2) |
| ISSN: | 1521-009X |
| Popis: | ABCG2 encodes the mitoxantrone resistance protein (MXR; breast cancer resistance protein), an ATP-binding cassette (ABC) efflux membrane transporter. Computational analysis of the ∼300 kb region of DNA surrounding ABCG2 (chr4:88911376-89220011, hg19) identified 30 regions with potential cis-regulatory capabilities. These putative regulatory regions were tested for their enhancer and suppressor activity in a human liver cell line using luciferase reporter assays. The in vitro enhancer and suppressor assays identified four regions that decreased gene expression and five regions that increased expression >1.6-fold. Four of five human hepatic in vitro enhancers were confirmed as in vivo liver enhancers using the mouse hydrodynamic tail vein injection assay. Two of the in vivo liver enhancers (ABCG2RE1 and ABCG2RE9) responded to 17β-estradiol or rifampin in human cell lines, and ABCG2RE9 had ChIP-seq evidence to support the binding of several transcription factors and the transcriptional coactivator p300 in human hepatocytes. This study identified genomic regions surrounding human ABCG2 that can function as regulatory elements, some with the capacity to alter gene expression upon environmental stimulus. The results from this research will drive future investigations of interindividual variation in ABCG2 expression and function that contribute to differences in drug response. |
| Databáze: | OpenAIRE |
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