Regional methylation of the 5′ end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells
Regional methylation of the 5′ end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells
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DOI：
10.1096/fj.14.11.1585
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发表时间：
2000-08-01
期刊：
影响因子：
4.8
通讯作者：
Dante, R
中科院分区：
文献类型：
--
作者：
Magdinier, F;Billard, LM;Dante, R
在非洲人中，特定启动子区域的去甲基化通常与基因激活相关;相反，CpG岛的密集甲基化导致基因沉默，可能由甲基-CpG结合蛋白介导。在细胞系和癌症中，组织特异性基因和肿瘤抑制基因表达的抑制似乎与这种超甲基化有关。乳腺癌易感基因BRCA 1的5'端嵌入一个长约2.7kb的大CpG岛中。在人类散发性乳腺癌中，BRCA 1的下调似乎与BRCA 1基因改变无关。Southern印迹分析和亚硫酸氢盐测序方法表明，BRCA 1 CpG岛是区域甲基化在所有分析的人类组织和非甲基化的配子，这表明DNA甲基化在控制基因表达的作用。因此，我们研究了甲基-CpG结合蛋白在BRCA 1基因表达调控中的潜在作用。在体外，部分甲基化的构建体含有这个区域强烈抑制基因表达的MeCP 2蛋白的存在下。此外，在分析的五种人类细胞系中，化学诱导的低甲基化与BRCA 1基因活化相关。这些数据表明，甲基-CpG结合蛋白可能与BRCA 1基因表达的控制和甲基-DNA结合蛋白可能参与哺乳动物细胞中的基因表达的调节。
In mammalians, demethylation of specific promoter regions often correlates with gene activation; inversely, dense methylation of CpG islands leads to gene silencing, probably mediated by methyl-CpG binding proteins. In cell Lines and cancers, inhibition of tissue-specific genes and tumor suppressor genes expression seems to be related to such hypermethylation. The 5' end of the breast cancer predisposition gene BRCA1 is embedded in a large CpG island of similar to 2.7 kb in length. In human sporadic breast cancers, the down-regulation of BRCA1 does not seem to be related to BRCA1 gene alterations. Southern blot analysis and the bisulfite sequencing method indicate that the BRCA1 CpG island is regionally methylated in all human tissues analyzed and unmethylated in the gametes, suggesting a role for DNA methylation in the control of gene expression. We have therefore investigated the potential role of methyl-CpG binding proteins in the regulation of BRCA1 gene expression. In vitro, partial methylation of constructs containing this region strongly inhibits gene expression in the presence of MeCP2 protein. Moreover, iu the five human cell lines analyzed, chemically induced hypomethylation is associated with BRCA1 gene activation. These data suggest that methyl-CpG binding proteins might be associated with the control of BRCA1 gene expression and that methyl-DNA binding proteins may participate in the regulation of gene expression in mammalian cells.