Promoter-dependent mechanism leading to selective hypomethylation within the 5′ region of gene MAGE-A1 in tumor cells
Promoter-dependent mechanism leading to selective hypomethylation within the 5′ region of gene MAGE-A1 in tumor cells
复制标题
DOI：
10.1128/mcb.24.11.4781-4790.2004
复制
发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Boon, T
中科院分区：
文献类型：
--
作者：
De Smet, C;Loriot, A;Boon, T
包括MAGE-A1在内的几个雄性生殖系特异基因依赖于DNA甲基化在正常体细胞组织中进行抑制。在全基因组去甲基化的过程中，这些基因在许多类型的肿瘤中被激活，这通常伴随着肿瘤的发生。我们发现，在表达MAGE-A1的肿瘤细胞中，5‘区域的甲基化程度明显低于该基因的其他部分。在这些肿瘤细胞中，导致这种位点特异性低甲基化的过程似乎不是永久性的，因为在体外甲基化的MAGE-A1序列中，稳定转染后不会发生去甲基化。然而，在这些细胞中，有一个过程抑制了MAGE-A1 5‘区的从头甲基化，因为未甲基化的MAGE-A1转基因基因在所有CPG中都经历了重新甲基化，但位于5’区的那些基因除外。这种甲基化的局部抑制似乎依赖于启动子的活性。我们的结论是，肿瘤细胞中MAGE-A1的位点特异性低甲基化依赖于短暂的去甲基化过程，随后由于转录因子的存在，局部持续地抑制再甲基化。
Several male germ line-specific genes, including MAGE-A1, rely on DNA methylation for their repression in normal somatic tissues. These genes become activated in many types of tumors in the course of the genomewide demethylation process which often accompanies tumorigenesis. We show that in tumor cells expressing MAGE-A1, the 5' region is significantly less methylated than the other parts of the gene. The process leading to this site-specific hypomethylation does not appear to be permanent in these tumor cells, since in vitromethylated MAGE-A1 sequences do not undergo demethylation after being stably transfected. However, in these cells there is a process that inhibits de novo methylation within the 5' region of MAGE-A1, since unmethylated MAGE-A1 transgenes undergo remethylation at all CpGs except those located within the 5' region. This local inhibition of methylation appears to depend on promoter activity. We conclude that the site-specific hypomethylation of MAGE-A1 in tumor cells relies on a transient process of demethylation followed by a persistent local inhibition of remethylation due to the presence of transcription factors.