Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 α/β and DNA methylation
Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 α/β and DNA methylation
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DOI：
10.1124/mol.107.039701
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发表时间：
2007-12-01
影响因子：
3.6
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Kikuchi, Ryota;Kusuhara, Hiroyuki;Sugiyama, Yuichi
尿酸盐转运蛋白 1 (URAT1/SLC22A12) 的表达仅限于肾脏的近端肾小管，负责尿酸盐的肾小管重吸收。为了阐明其组织特异性表达的机制，研究了 hURAT1 和 mUrat1 基因的转录调控。报告基因检测显示，肝细胞核因子 1 α (HNF1 α) 和 HNF1 β 正向调节 URAT1 基因的最小启动子活性。电泳迁移率变动分析显示 HNF1 α 和/或 HNF1 β 与 hURAT1 启动子中的 HNF1 基序结合。此外，与野生型小鼠相比，Hnf1α缺失小鼠肾脏中Urat1的mRNA表达量降低，证实了HNF1α在URAT1基因组成型表达中不可或缺的作用。研究还表明，mUrat1 的近端启动子区域在肝和肾髓质中高度甲基化，而该区域在肾皮质中相对低甲基化。这些甲基化谱与肾皮质中 mUrat1 的近端小管限制表达非常一致。总而言之，这些结果强烈表明 URAT1 基因的组织特异性表达受到 HNF1 α/HNF1 β 异二聚体的转录激活和 DNA 甲基化的抑制的协调调节。
Expression of Urate transporter 1 (URAT1/SLC22A12) is restricted to the proximal tubules in the kidney, where it is responsible for the tubular reabsorption of urate. To elucidate the mechanism underlying its tissue-specific expression, the transcriptional regulation of the hURAT1 and mUrat1 genes was investigated. Hepatocyte nuclear factor 1 alpha (HNF1 alpha) and HNF1 beta positively regulate minimal promoter activity of the URAT1 gene as shown by reporter gene assays. Electrophoretic mobility shift assays revealed binding of HNF1 alpha and/or HNF1 beta to the HNF1 motif in the hURAT1 promoter. Furthermore, the mRNA expression of Urat1 is reduced in the kidneys of Hnf1 alpha-null mice compared with wild-type mice, confirming the indispensable role of HNF1 alpha in the constitutive expression of URAT1 genes. It was also shown that the proximal promoter region of mUrat1 was hypermethylated in the liver and kidney medulla, whereas this region was relatively hypomethylated in the kidney cortex. These methylation profiles are in a good agreement with the proximal tubule-restricted expression of mUrat1 in the kidney cortex. Taken together, these results strongly suggest that tissue-specific expression of the URAT1 genes is coordinately regulated by the transcriptional activation by HNF1 alpha/HNF1 beta heterodimer and repression by DNA methylation.