Genome-wide analysis of epigenetic signatures for kidney-specific transporters
Genome-wide analysis of epigenetic signatures for kidney-specific transporters
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DOI：
10.1038/ki.2010.176
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发表时间：
2010-09-01
影响因子：
19.6
通讯作者：
Shiota, Kunio
中科院分区：
文献类型：
--
作者：
Kikuchi, Ryota;Yagi, Shintaro;Shiota, Kunio
DNA甲基化依赖的基因沉默是基因表达的表观遗传调控中最具特征的机制之一。该过程被认为影响肝细胞核因子1（HNF 1）反式激活肝和肾中有机阴离子转运蛋白表达的能力。为了进一步评估这一点，我们分析了282小鼠溶质载体转运蛋白，通过检查其转录起始位点附近的区域，使用限制性标签介导的扩增来确定肝脏和肾脏之间的T-DMR差异，以确定组织依赖性差异甲基化区域（T-DMR）。其中42例与肾脏中低甲基化但肝脏中高甲基化的T-DMR标签相关。计算分析发现，一个典型的HNF 1结合基序内的13个载体，包括氨基酸转运蛋白Slc6a19，Slc6a20，Slc7a8和Slc7a9的启动子区域，主要在肾脏中表达。亚硫酸氢盐基因组测序发现，与肝脏相比，与T-DMR标签相邻的CpG二核苷酸在肾脏中低甲基化。Hnf1 α启动子区域本身含有在肝脏和肾脏中低甲基化但在大脑中高甲基化的T-DMR，这与Hnf1 α的组织分布一致。总之，我们的研究结果表明，在肾脏特异性表达的氨基酸转运蛋白，从而确定其主调节因子，Hnf1 α，及其与下游基因的相互作用的组织分布的DNA甲基化的核心作用。Kidney International（2010）78，569 - 577; doi：10.1038/ki.2010.176; 2010年6月16日在线发表
DNA methylation-dependent gene silencing is one of the most characterized mechanisms in epigenetic regulation of gene expression. This process is thought to influence the ability of hepatocyte nuclear factor 1 (HNF1) to transactivate organic anion transporter expression in the liver and kidney. To evaluate this further we profiled 282 mouse solute carrier transporters by examining regions near their transcription start sites for tissue-dependent differentially methylated regions (T-DMR) using restriction tag-mediated amplification to determine T-DMR disparity between the liver and kidney. Forty-two of these were associated with T-DMR tags hypomethylated in the kidney but hypermethylated in the liver. Computational analysis found a canonical HNF1-binding motif within 1 kbp of the promoter region of 13 carriers including the amino acid transporters Slc6a19, Slc6a20, Slc7a8 and Slc7a9; all expressed predominantly in the kidney. Bisulfite genomic sequencing found that CpG dinucleotides neighboring the T-DMR tags were hypomethylated in the kidney compared with the liver. The Hnf1 alpha promoter region itself contained a T-DMR hypomethylated in the liver and kidney but hypermethylated in the cerebrum, consistent with the tissue distribution of Hnf1 alpha. Taken together, our results show a central role of DNA methylation in the kidney-specific expression of amino acid transporters thus determining both the tissue distribution of their master regulator, Hnf1 alpha, and its interaction with downstream genes. Kidney International (2010) 78, 569-577; doi:10.1038/ki.2010.176; published online 16 June 2010