Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus.
Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus.
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DOI：
10.1158/0008-5472.can-10-0765
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Baylin SB
中科院分区：
文献类型：
--
作者：
Easwaran HP;Van Neste L;Cope L;Sen S;Mohammad HP;Pageau GJ;Lawrence JB;Herman JG;Schuebel KE;Baylin SB
异常的启动子 DNA 高甲基化和抑制性染色质构成了癌症中基因失活的常见机制。人们对剖析这种异常沉默背后的机制非常感兴趣。研究表明肿瘤细胞染色质核组织的变化以及异常甲基化与邻近基因的长距离沉默的关联。此外，某些肿瘤显示出启动子甲基化的高发生率，称为 CpG 岛甲基化表型 (CIMP)。在这里，我们分析了基因在高甲基化非活性状态与非甲基化活性状态下核染色质结构的作用及其与长程沉默和 CIMP 的关系。在结直肠癌细胞系中使用活性/抑制性染色质标记的联合免疫染色和 FISH，我们发现这些基因的异常沉默不需要将它们定位在异染色质区域就可以发生。重要的是，即使与邻近基因的长程表观遗传沉默相关，高甲基化的发生也与其常染色质或异染色质位置无关。总之，这些结果表明，在癌症中，单个基因或基因簇的启动子染色质周围的广泛变化可能局部发生，而不偏好核位置和/或导致重新定位。这些发现对于理解癌症中核组织和基因表达模式之间的关系具有重要意义。
Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of gene inactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal silencing. Studies have shown changes in nuclear organization of chromatin in tumor cells as well as association of aberrant methylation with long range silencing of neighboring genes. Further, certain tumors show a high incidence of promoter methylation termed as the CpG island methylator phenotype (CIMP). Here we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive versus non-methylated active states and its relation with long range silencing and CIMP. Using combined immunostaining for active/repressive chromatin marks and FISH in colorectal cancer cell lines we show that aberrant silencing of these genes occurs without requirement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even when associated with long-range epigenetic silencing of neighboring genes, occurs independent of their euchromatic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes around promoter chromatin of individual genes, or gene clusters, can potentially occur locally without preference for nuclear position and/or causing repositioning. These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer.