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Received for publication April 10, 2006.
Revised June 8, 2006.
Accepted for publication June 20, 2006.
/
and DNA Methylation
Human Organic Anion Transporter 3 (hOAT3/SLC22A8) is predominantly expressed in the proximal tubules of the kidney, and plays a major role in the urinary excretion of a variety of organic anions. The promoter region of hOAT3 was characterized to elucidate the mechanism underlying the tissue specific expression of hOAT3. The minimal promoter of hOAT3 was identified to be located approximately 300 bp upstream of the transcriptional start site, where there are canonical TATA and HNF1 binding motifs, which are conserved in the rodent Oat3 genes. Transactivation assays revealed that HNF1
and HNF1
markedly increased hOAT3 promoter activity, where the transactivation potency of HNF1 was lower than that of HNF1. Mutations in the HNF1 binding motif prevented the transactivation. Electrophoretic mobility shift assays demonstrated binding of the HNF1/HNF1 homodimer or HNF1/HNF1 heterodimer to the hOAT3 promoter. It was also demonstrated that the promoter activity of hOAT3 is repressed by DNA methylation. Moreover, the expression of hOAT3 was activated de novo by forced expression of HNF1 alone or both HNF1 and HNF1 together with the concomitant DNA demethylation in HEK293 cells that lack expression of endogenous HNF1 and HNF1, whereas forced expression of HNF1 alone could not activate the expression of hOAT3. This suggests a synergistic action of the HNF1/HNF1 homodimer or HNF1/HNF1 heterodimer and DNA demethylation for the constitutive expression of hOAT3. These results indicate that the tissue specific expression of hOAT3 might be regulated by the concerted effect of genetic (HNF1 and HNF1) and epigenetic (DNA methylation) factors.
Key words:
Promoter analysis, Organic anion, Regulation - transcriptional
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