title: Epigenetic regulation is a crucial factor in the repression of UGT1A1 expression in the human kidney.
abstract: Human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 catalyzes the metabolism of numerous clinically and pharmacologically important compounds, such as bilirubin and SN-38. UGT1A1 is predominantly expressed in the liver and intestine but not in the kidney. The purpose of this study was to uncover the mechanism of the tissue-specific expression of UGT1A1, focusing on its epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region near the UGT1A1 promoter (-85 to +40) was hypermethylated (83%) in the kidney, whereas it was hypomethylated (37%) in the liver. A chromatin immunoprecipitation assay demonstrated that histone H3 near the promoter was hypoacetylated in the kidney but hyperacetylated in the liver; this hyperacetylation was accompanied by the recruitment of hepatocyte nuclear factor (HNF) 1α to the promoter. The UGT1A1 promoter in human kidney-derived HK-2 cells that do not express UGT1A1 was fully methylated, but this promoter was relatively unmethylated in human liver-derived HuH-7 cells that express UGT1A1. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methylation, resulted in an increase of UGT1A1 mRNA expression in both cell types, but the increase was much larger in HK-2 cells than in HuH-7 cells. The transfection of an HNF1α expression plasmid into the HK-2 cells resulted in an increase of UGT1A1 mRNA only in the presence of 5-aza-dC. In summary, we found that DNA hypermethylation, along with histone hypoacetylation, interferes with the binding of HNF1α, resulting in the defective expression of UGT1A1 in the human kidney. Thus, epigenetic regulation is a crucial determinant of tissue-specific expression of UGT1A1.
authors: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors: Shingo
authors: S
authors: Oda
authors: Tatsuki
authors: T
authors: Fukami
authors: Tsuyoshi
authors: T
authors: Yokoi
authors: Miki
authors: M
authors: Nakajima
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones; D000099148:UGT1A1 Enzyme