CPG methylation within the 5′ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site
CPG methylation within the 5′ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site
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DOI：
10.1038/sj.onc.1201630
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发表时间：
1998-03-05
期刊：
影响因子：
8
通讯作者：
Archer, TK
中科院分区：
文献类型：
--
作者：
Mancini, DN;Rodenhiser, DI;Archer, TK
乳腺癌是一种遗传性疾病，由多种基因（包括BRCA 1和BRCA 2）中的一系列生殖系和/或体细胞DNA变化引起，DNA修饰已被证明通过包括DNA甲基化在内的多种机制发生，在某些情况下，5'调控区内CpG的异常甲基化导致基因活性抑制。在这份报告中，我们描述了BRCA 1基因调控区的DNA甲基化模式的变化，我们没有发现BRCA 1启动子内的CpG甲基化在各种正常人体组织中的证据，然而，筛选一系列随机抽样的乳腺癌显示存在CpG甲基化邻近BRCA 1转录起始位点。一个这样的甲基化CpG发生在假定的CREB（cAMP-反应元件结合）转录因子结合位点，用甲基化和未甲基化的BRCA 1/CREB结合位点寡核苷酸进行的凝胶移位分析证明该位点对位点特异性CpG甲基化敏感，这些数据表明，BRCA 1基因座调控序列的异常DNA甲基化可能在转录失活中发挥作用，BRCA 1基因在乳腺肿瘤亚克隆中的表达，本研究首次提出了DNA甲基化在乳腺癌BRCA 1转录失活中的作用。
Breast cancer is a genetic disease arising from a series of germ-line and/or somatic DNA changes in a variety of genes, including BRCA1 and BRCA2, DNA modifications have been shown to occur by a number of mechanisms that include DNA methylation, In some cases, the aberrant methylation of CpGs within 5' regulatory regions has led to suppression of gene activity. In this report we describe a variation in the pattern of DNA methylation within the regulatory region of the BRCA1 gene, We found no evidence of methylation at CpGs within the BRCA1 promoter in a variety of normal human tissues, However, screening of a series of randomly sampled breast carcinomas revealed the presence of CpG methylation adjacent to the BRCA1 transcription start site. One such methylated CpG occurs at a putative CREB (cAMP-responsive element binding) transcription factor binding site in the BRCA1 promoter, Gelshift assays with methylated and unmethylated BRCA1/CREB binding site oligonucleotides demonstrate that this site is sensitive to site-specific CpG methylation, These data suggest that aberrant DNA methylation at regulatory sequences in the BRCA1 locus may play a role in the transcriptional inactivation of the BRCA1 gene within subclones of breast tumors, This study represents the first evidence suggesting a role for DNA methylation in the transcriptional inactivation of the BRCA1 in human breast cancer.