MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma.
MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma.
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DOI：
10.1186/1476-4598-10-124
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发表时间：
2011-09-30
期刊：
影响因子：
37.3
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Zhang Z;Tang H;Wang Z;Zhang B;Liu W;Lu H;Xiao L;Liu X;Wang R;Li X;Wu M;Li G
DNA甲基化的扰动在癌症中很常见，并已成为肿瘤发生的重要机制。为了确定DNA甲基化是如何在原发性胶质瘤基因组中被修饰的，我们使用甲基DNA免疫沉淀（MeDIP）和Nimblegen CpG启动子微阵列来鉴定原发性胶质瘤和正常脑组织样本之间DNA甲基化序列的差异。使用medip芯片技术研究胶质瘤和正常脑组织的全基因组差异甲基化模式。随后，通过Sequenom的MassARRAY系统，在40个胶质瘤样本和4个细胞系中验证了8个候选基因的启动子甲基化状态。然后，通过染色质免疫沉淀和实时荧光定量PCR检测这些基因的表观遗传调控表达及其可能的机制。在胶质瘤中共鉴定出524个高甲基化区和104个低甲基化区。其中，216个高甲基化区域和60个低甲基化区域被定位到与多种重要细胞过程相关的已知基因的启动子上。8个启动子高甲基化基因（ANKDD1A、GAD1、HIST1H3E、PCDHA8、PCDHA13、PHOX2B、SIX3和SST）在原发性胶质瘤和细胞系中得到证实。异常启动子甲基化和组蛋白修饰的改变与它们在胶质瘤中的表达减少有关。此外，我们发现在胶质瘤中位于22q11.2的miR-185位点的杂合性缺失（LOH），诱导miR-185过表达降低了整体DNA甲基化，并通过直接靶向DNA甲基转移酶诱导胶质瘤细胞中启动子高甲基化基因的表达1。这些全面的数据可能为人类胶质瘤的表观遗传发病机制提供新的见解。
Perturbation of DNA methylation is frequent in cancers and has emerged as an important mechanism involved in tumorigenesis. To determine how DNA methylation is modified in the genome of primary glioma, we used Methyl-DNA immunoprecipitation (MeDIP) and Nimblegen CpG promoter microarrays to identify differentially DNA methylation sequences between primary glioma and normal brain tissue samples. MeDIP-chip technology was used to investigate the whole-genome differential methylation patterns in glioma and normal brain tissues. Subsequently, the promoter methylation status of eight candidate genes was validated in 40 glioma samples and 4 cell lines by Sequenom's MassARRAY system. Then, the epigenetically regulated expression of these genes and the potential mechanisms were examined by chromatin immunoprecipitation and quantitative real-time PCR. A total of 524 hypermethylated and 104 hypomethylated regions were identified in glioma. Among them, 216 hypermethylated and 60 hypomethylated regions were mapped to the promoters of known genes related to a variety of important cellular processes. Eight promoter-hypermethylated genes (ANKDD1A, GAD1, HIST1H3E, PCDHA8, PCDHA13, PHOX2B, SIX3, and SST) were confirmed in primary glioma and cell lines. Aberrant promoter methylation and changed histone modifications were associated with their reduced expression in glioma. In addition, we found loss of heterozygosity (LOH) at the miR-185 locus located in the 22q11.2 in glioma and induction of miR-185 over-expression reduced global DNA methylation and induced the expression of the promoter-hypermethylated genes in glioma cells by directly targeting the DNA methyltransferases 1. These comprehensive data may provide new insights into the epigenetic pathogenesis of human gliomas.
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影响因子：
3.5
作者：
Baylin, SB;Esteller, M;Herman, JG
通讯作者：
Herman, JG
影响因子：
11.5
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Fukushima, T;Katayama, Y;Komine, C
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作者：
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4.6
作者：
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