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首页> 外文期刊>Genomics >Methylation patterns of the human beta-glucuronidase gene locus: boundaries of methylation and general implications for frequent point mutations at CpG dinucleotides.
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Methylation patterns of the human beta-glucuronidase gene locus: boundaries of methylation and general implications for frequent point mutations at CpG dinucleotides.

机译：人类β-葡萄糖醛酸糖苷酶基因位点的甲基化模式：甲基化的边界和CpG二核苷酸频繁点突变的一般含义。

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Methylation of CpG islands spanning promoter regions is associated with control of gene expression, although it is unclear what mechanisms define the boundaries between methylated and unmethylated regions in the genome. Methylation of genomic DNA in mammals also affects the frequency of inherited diseases by predisposing them to CpG mutations. To gain insight into these issues, we investigated patterns of cytosine methylation on almost the entire beta-glucuronidase gene (GUSB) from normal leukocyte DNAs by bisulfite genomic sequencing. We mapped the boundaries of methylation that flank the 5'- and 3'-ends of the CpG island region, and correlated methylation status with transitional mutations at CpG sites. GenBank sequence analyses showed that the CpG island of human GUSB is juxtaposed with multiple Alu repeats and also includes multiple Sp1 sites upstream and downstream of the transcription start, which has been suggested to prevent CpG islands from becoming methylated. We show that cytosine methylation is extensive across the entire gene except for CpG sites in the proximal promoter region, exon 1, and part of intron 1; the unmethylated CpG island is embedded between densely methylated flanking regions containing multiple Alu repeats; a sharp boundary separates the methylated and unmethylated regions of the 5'-flank of the CpG island, but a gradual change in methylation density over 1.0 kb is observed in the 3'-flank of the CpG island; boundaries of the 5'-end and 3'-end of the CpG island contain multiple Sp1 sites in addition to Alu repeats; methylation in both strands is symmetrical except at the boundary regions between methylated and unmethylated regions; and nonmethylation of exon 1 correlates with the absence of transitional mutations at CpG sites in exon 1.
机译：跨启动子区域的CpG岛的甲基化与基因表达的控制有关，尽管尚不清楚什么机制定义了基因组中甲基化和非甲基化区域之间的边界。哺乳动物中基因组DNA的甲基化也会使遗传疾病易患CpG突变，从而影响遗传疾病的发生频率。为了深入了解这些问题，我们通过亚硫酸氢盐基因组测序研究了正常白细胞DNA中几乎整个β-葡糖醛酸糖苷酶基因（GUSB）上胞嘧啶甲基化的模式。我们绘制了位于CpG岛区域5'和3'末端的甲基化边界，并将甲基化状态与CpG位点的过渡突变相关联。 GenBank序列分析表明，人GUSB的CpG岛与多个Alu重复序列并列，并且在转录起点的上游和下游还包括多个Sp1位点，这表明可以防止CpG岛甲基化。我们显示，除了近端启动子区域，外显子1和内含子1的一部分中的CpG位点外，胞嘧啶甲基化广泛分布于整个基因。未甲基化的CpG岛嵌入在含有多个Alu重复序列的密集甲基化侧翼区域之间;尖锐的边界将CpG岛5'侧翼的甲基化和未甲基化区域分开，但是在CpG岛的3'侧翼中观察到甲基化密度在1.0 kb以上逐渐变化。 CpG岛的5'端和3'端的边界除Alu重复序列外还包含多个Sp1位点;除了在甲基化区域和未甲基化区域之间的边界区域外，两条链中的甲基化都是对称的;外显子1的非甲基化与外显子1的CpG位点不存在过渡突变有关。

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