Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene
Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene
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DOI：
10.1038/35013100
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发表时间：
2000-05-25
期刊：
影响因子：
64.8
通讯作者：
Felsenfeld, G
中科院分区：
文献类型：
--
作者：
Bell, AC;Felsenfeld, G
胰岛素样生长因子 2 (Igf2) 和 H19 基因的表达受到印记。尽管这些邻近基因共享一个增强子(1)，但 H19 仅从母系等位基因表达，而 Igf2 仅从父系遗传等位基因表达(2,3)。 H19 上游的父本特异性甲基化区域似乎是这些基因印记所需的表观遗传标记位点(4,5)。该区域内的缺失会导致 H19 和 Igf2 的印记丢失（参考文献 5）。在这里，我们证明这个甲基化区域包含一种阻止增强子活性的元素。该元件的活性取决于脊椎动物增强子阻断蛋白 CTCF。 CTCF 结合位点内 CpG 的甲基化消除了 CTCF 的体外结合，而这些位点的删除导致体内增强子阻断活性的丧失，从而允许基因表达。这种 CTCF 依赖性增强子阻断元件充当绝缘体。我们认为它控制 Igf 2 的印记。该绝缘体的活性通过父本等位基因的特定 DNA 甲基化而限制于母本等位基因。我们的结果表明，DNA 甲基化可以通过调节增强子边界来调节增强子对基因启动子的访问，从而控制基因表达。
The expression of the insulin-like growth factor 2 (Igf2) and H19 genes is imprinted. Although these neighbouring genes share an enhancer(1), H19 is expressed only from the maternal allele, and Igf2 only from the paternally inherited allele(2,3). A region of paternal-specific methylation upstream of H19 appears to be the site of an epigenetic mark that is required for the imprinting of these genes(4,5). A deletion within this region results in loss of imprinting of both H19 and Igf2 (ref. 5). Here we show that this methylated region contains an element that blocks enhancer activity. The activity of this element is dependent upon the vertebrate enhancer-blocking protein CTCF. Methylation of CpGs within the CTCF-binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. We suggest that it controls imprinting of Igf 2. The activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. Our results reveal that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary.