Role of DNA Methylation and Histone H3 Lysine 27 Methylation in Tissue-Specific Imprinting of Mouse Grb10
Role of DNA Methylation and Histone H3 Lysine 27 Methylation in Tissue-Specific Imprinting of Mouse Grb10
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DOI：
10.1128/mcb.01329-06
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发表时间：
2006-11
影响因子：
5.3
通讯作者：
Yoko Yamasaki-Ishizaki;Tomohiko Kayashima;C. K. Mapendano;H. Soejima;T. Ohta;H. Masuzaki;A. Kinoshita;T. Urano;K. Yoshiura;N. Matsumoto;T. Ishimaru;T. Mukai;N. Niikawa;T. Kishino
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文献类型：
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作者：
Yoko Yamasaki-Ishizaki;Tomohiko Kayashima;C. K. Mapendano;H. Soejima;T. Ohta;H. Masuzaki;A. Kinoshita;T. Urano;K. Yoshiura;N. Matsumoto;T. Ishimaru;T. Mukai;N. Niikawa;T. Kishino
摘要小鼠Grb10是一个组织特异性印迹基因，具有启动子特异性表达。在大多数组织中，Grb10仅由母亲等位基因的主要类型启动子表达，而在大脑中，它主要从父亲等位基因的脑型启动子表达。这种在大脑和其他组织中的相互印记表达被认为是由DNA甲基化和聚梳组(PcG)蛋白Eed调节的。为了研究PcG蛋白的DNA甲基化和染色质重塑如何协调Grb10的组织特异性印迹，我们分析了与培养的脑细胞中Grb10表达相关的表观遗传修饰。逆转录聚合酶链式反应分析表明，Grb10在父亲脑中的印迹表达暗示了父亲脑型启动子的神经元特异性和发育阶段特异性表达，而在胶质细胞和成纤维细胞中，Grb10的表达来自母体主型启动子。细胞特异性印迹表达与启动子中的等位基因特异性DNA甲基化没有直接关系，因为主要类型的启动子保持双等位低甲基化，而脑型启动子的配子DNA甲基化在分化过程中保持不变。组蛋白修饰分析表明，组蛋白H3赖氨酸4和H3赖氨酸9的等位基因甲基化与脑型启动子的配子DNA甲基化有关，而受Eed PcG复合体调控的H3赖氨酸27的甲基化发生在父亲的主要类型启动子中，对应于其等位基因特异性沉默。在这里，我们提出了一个分子模型，在细胞分化过程中，配子DNA甲基化和PcG蛋白对染色质的重塑导致了胚胎组织中的组织特异性印记。
ABSTRACT Mouse Grb10 is a tissue-specific imprinted gene with promoter-specific expression. In most tissues, Grb10 is expressed exclusively from the major-type promoter of the maternal allele, whereas in the brain, it is expressed predominantly from the brain type promoter of the paternal allele. Such reciprocally imprinted expression in the brain and other tissues is thought to be regulated by DNA methylation and the Polycomb group (PcG) protein Eed. To investigate how DNA methylation and chromatin remodeling by PcG proteins coordinate tissue-specific imprinting of Grb10, we analyzed epigenetic modifications associated with Grb10 expression in cultured brain cells. Reverse transcriptase PCR analysis revealed that the imprinted paternal expression of Grb10 in the brain implied neuron-specific and developmental stage-specific expression from the paternal brain type promoter, whereas in glial cells and fibroblasts, Grb10 was reciprocally expressed from the maternal major-type promoter. The cell-specific imprinted expression was not directly related to allele-specific DNA methylation in the promoters because the major-type promoter remained biallelically hypomethylated regardless of its activity, whereas gametic DNA methylation in the brain type promoter was maintained during differentiation. Histone modification analysis showed that allelic methylation of histone H3 lysine 4 and H3 lysine 9 were associated with gametic DNA methylation in the brain type promoter, whereas that of H3 lysine 27 regulated by the Eed PcG complex was detected in the paternal major-type promoter, corresponding to its allele-specific silencing. Here, we propose a molecular model that gametic DNA methylation and chromatin remodeling by PcG proteins during cell differentiation cause tissue-specific imprinting in embryonic tissues.