Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines.
Azacytidine and decitabine induce gene-specific and non-random DNA demethylation in human cancer cell lines.
复制标题
DOI：
10.1371/journal.pone.0017388
复制
发表时间：
2011-03-07
期刊：
影响因子：
3.7
通讯作者：
Brueckner B
中科院分区：
文献类型：
--
作者：
Hagemann S;Heil O;Lyko F;Brueckner B
DNA甲基转移酶抑制剂氮杂胞苷和地西他滨代表了表观遗传癌症治疗的原型药物。为了表征氮杂胞苷和地西他滨的去甲基化活性，我们用这两种药物治疗结肠癌和白血病细胞，并对超过14，000个基因启动子进行基于阵列的DNA甲基化分析。此外，将药物诱导的去甲基化与缺乏DNA甲基转移酶1（DNMT1）和DNMT3B的同基因结肠癌细胞的甲基化模式进行了比较。我们发现，药物诱导的去甲基化模式是高度特异性的，非随机的和可重复的，表明复制后特定位点的靶向再甲基化。相应地，我们发现CG岛内的CG二核苷酸优先重甲基化，表明DNA序列背景的作用。我们还确定了一个基因的子集，从来没有去甲基化的药物治疗，无论是在结肠癌或白血病细胞系。这些去甲基化抗性基因富含胚胎干细胞中的Polycomb抑制复合物2组分和去甲基化基因中不存在的转录因子结合基序。我们的研究结果提供了详细的见解氮杂胞苷和地西他滨诱导的DNA甲基化模式，并建议复杂的调控机制在药物诱导的DNA去甲基化的参与。
The DNA methyltransferase inhibitors azacytidine and decitabine represent archetypal drugs for epigenetic cancer therapy. To characterize the demethylating activity of azacytidine and decitabine we treated colon cancer and leukemic cells with both drugs and used array-based DNA methylation analysis of more than 14,000 gene promoters. Additionally, drug-induced demethylation was compared to methylation patterns of isogenic colon cancer cells lacking both DNA methyltransferase 1 (DNMT1) and DNMT3B. We show that drug-induced demethylation patterns are highly specific, non-random and reproducible, indicating targeted remethylation of specific loci after replication. Correspondingly, we found that CG dinucleotides within CG islands became preferentially remethylated, indicating a role for DNA sequence context. We also identified a subset of genes that were never demethylated by drug treatment, either in colon cancer or in leukemic cell lines. These demethylation-resistant genes were enriched for Polycomb Repressive Complex 2 components in embryonic stem cells and for transcription factor binding motifs not present in demethylated genes. Our results provide detailed insights into the DNA methylation patterns induced by azacytidine and decitabine and suggest the involvement of complex regulatory mechanisms in drug-induced DNA demethylation.
登录
查看更多内容
影响因子：
4.5
作者：
Grönniger E;Weber B;Heil O;Peters N;Stäb F;Wenck H;Korn B;Winnefeld M;Lyko F
通讯作者：
Lyko F
影响因子：
3
作者：
MOMPARLER, RL;SAMSON, J;RIVARD, GE
通讯作者：
RIVARD, GE
DOI：
10.1073/pnas.0604602103
发表时间：
2006-09-19
影响因子：
11.1
作者：
Egger, Gerda;Jeong, Shinwu;Liang, Gangning
通讯作者：
Liang, Gangning
影响因子：
30.8
作者：
Jones, PL;Veenstra, GJC;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA