DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression
DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression
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DOI：
10.1101/gr.074070.107
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发表时间：
2008-12-01
期刊：
影响因子：
7
通讯作者：
Shiota, Kunio
中科院分区：
文献类型：
--
作者：
Yagi, Shintaro;Hirabayashi, Keiji;Shiota, Kunio
DNA甲基化在许多真核生物中是一种重要的表观遗传调控机制，尽管在哺乳动物基因组中DNA甲基化在基因表达调控中的作用程度还知之甚少。我们开发了D -REAM，这是一种在小鼠组织和细胞中利用限制性标签介导的扩增进行全基因组DNA甲基化分析的方法，用于组织依赖性差异甲基化区域（T -DMR）的分析。使用覆盖从 -6到2.5kb区域（约30,000个转录起始位点）的小鼠启动子芯片，我们发现与大脑相比，肝脏中有超过3000个T -DMRs呈低甲基化。肝脏的DNA甲基化图谱不同于肾脏和脾脏。这种低甲基化图谱标记了在肝脏中特异性表达的基因，包括关键转录因子如Hnf1a和Hnf4a。具有T -DMRs的基因，尤其是那些缺乏CpG岛以及在其启动子中具有HNF -1A结合基序的基因，在其组织特异性表达和肝脏低甲基化状态之间显示出良好的相关性。位于转录起始位点下游的T -DMRs也显示出组织特异性基因表达。这些数据表明，通过DNA甲基化组织图谱分析可以阐明组织特异性基因功能的多层次调控。
DNA methylation constitutes an important epigenetic regulation mechanism in many eukaryotes, although the extent of DNA methylation in the regulation of gene expression in the mammalian genome is poorly understood. We developed D-REAM, a genome-wide DNA methylation analysis method for tissue-dependent and differentially methylated region (T-DMR) profiling with restriction tag-mediated amplification in mouse tissues and cells. Using a mouse promoter tiling array covering a region from -6 to 2.5 kb (similar to 30,000 transcription start sites), we found that over 3000 T-DMRs are hypomethylated in liver compared to cerebrum. The DNA methylation profile of liver was distinct from that of kidney and spleen. This hypomethylation profile marked genes that are specifically expressed in liver, including key transcription factors such as Hnf1a and Hnf4a. Genes with T-DMRs, especially those lacking CpG islands and those with HNF-1A binding motifis in their promoters, showed good correlation between their tissue-specific expression and liver hypomethylation status. T-DMRs located downstream from their transcription start sites also showed tissue-specific gene expression. These data indicate that multilayered regulation of tissue-specific gene function could be elucidated by DNA methylation tissue profiling.