Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing.
Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing.
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DOI：
10.1186/1471-2164-8-131
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发表时间：
2007-05-24
期刊：
影响因子：
4.4
通讯作者：
Plass C
中科院分区：
文献类型：
--
作者：
Wu J;Wang SH;Potter D;Liu JC;Smith LT;Wu YZ;Huang TH;Plass C
先前对单个基因的研究表明，在一种自我执行的方式中，组蛋白3赖氨酸9（二甲基-H3 K9）的二甲基化和DNA甲基化合作，以维持非活性基因的抑制模式。不太清楚的是，这种合作是否普遍存在于哺乳动物基因组中，如小鼠基因组。在这里，我们使用表观基因组工具，同时询问染色质修饰和DNA甲基化在小鼠白血病细胞系，L1210。通过全局CpG岛阵列和定制小鼠启动子阵列分析来分析H3 K9上的组蛋白修饰和L1210中的DNA甲基化。我们使用染色质免疫沉淀微阵列（ChIP芯片）来检测乙酰-H3 K9和二甲基-H3 K9。我们发现乙酰-H3 K9在不同染色质位置的相对水平比二甲基-H3 K9具有更宽的分布范围。然后，我们使用差异甲基化杂交（DMH）和限制性标志基因组扫描（RLGS）来分析ChIP芯片所研究的相同靶标的DNA甲基化状态。表观基因组分析的结果，这已被独立证实的个别基因座，DNA甲基化和组蛋白乙酰化之间的负相关关系，在调节基因沉默。与之前的概念相反，二甲基-H3 K9在指定测试基因的沉默方面似乎不太明显。本研究表明，在L1210白血病细胞中，组蛋白修饰和DNA甲基化在维持基因沉默中存在多种关系。乙酰基-H3 K9在调节基因沉默中显示出DNA甲基化和组蛋白乙酰化之间的反比关系。然而，二甲基-H3 K9似乎与启动子甲基化的关系不太明显。同时，表观基因组学工具的组合有助于理解表观遗传调控的异质性，这可能会进一步扩大我们从单基因研究中积累的视野。
Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Less clear is whether this cooperation is generalized in mammalian genomes, such as mouse genome. Here we use epigenomic tools to simultaneously interrogate chromatin modifications and DNA methylation in a mouse leukemia cell line, L1210. Histone modifications on H3K9 and DNA methylation in L1210 were profiled by both global CpG island array and custom mouse promoter array analysis. We used chromatin immunoprecipitation microarray (ChIP-chip) to examine acetyl-H3K9 and dimethyl-H3K9. We found that the relative level of acetyl-H3K9 at different chromatin positions has a wider range of distribution than that of dimethyl-H3K9. We then used differential methylation hybridization (DMH) and the restriction landmark genome scanning (RLGS) to analyze the DNA methylation status of the same targets investigated by ChIP-chip. The results of epigenomic profiling, which have been independently confirmed for individual loci, show an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing. In contrast to the previous notion, dimethyl-H3K9 seems to be less distinct in specifying silencing for the genes tested. This study demonstrates in L1210 leukemia cells a diverse relationship between histone modifications and DNA methylation in the maintenance of gene silencing. Acetyl-H3K9 shows an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing as expected. However, dimethyl-H3K9 seems to be less distinct in relation to promoter methylation. Meanwhile, a combination of epigenomic tools is of help in understanding the heterogeneity of epigenetic regulation, which may further our vision accumulated from single-gene studies.
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