DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner
DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner
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DOI：
10.1101/gad.1470906
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发表时间：
2006-12-15
影响因子：
10.5
通讯作者：
Okano, Masaki
中科院分区：
文献类型：
--
作者：
Oda, Masaaki;Yamagiwa, Akiko;Okano, Masaki
DNA甲基化是胚胎发生过程中控制发育基因调控的主要表观遗传机制，但其调控机制尚不清楚。在本报告中，我们发现与x连锁同源盒基因簇Rhox相关的CpG岛在胚胎外滋养外胚层中高度表达，在小鼠着床后发育过程中以阶段特异性和谱系特异性的方式差异甲基化。DNA甲基化转移酶Dnmt3a和Dnmt3b失活后，胚胎中DNA甲基化的建立和Rhox簇基因的沉默都被取消。Dnmt3a和Dnmt3b是启动新生DNA甲基化所必需的。Rhox位点的dnmt3依赖性cpg岛甲基化扩展到一个包含Rhox簇和周围基因的大基因组区域（类似于1 Mb）。利用缺乏DNA甲基转移酶的胚胎干（ES）细胞进行的互补实验表明，Dnmt3a和Dnmt3b的cpg岛甲基化仅限于这个大的基因组区域内，不影响其外的邻近基因，暗示存在区域特异性边界。我们的研究结果表明，DNA甲基化在胚胎发生过程中远程基因沉默和谱系特异性沉默中都起着重要作用。
DNA methylation is a major epigenetic mechanism that has been suggested to control developmental gene regulation during embryogenesis, but its regulatory mechanisms remain unclear. In this report, we show that CpG islands associated with the X-linked homeobox gene cluster Rhox, which is highly expressed in the extraembryonic trophectoderm, are differentially methylated in a stage- and lineage-specific manner during the post-implantation development of mice. Inactivation of both Dnmt3a and Dnmt3b, DNA methyltransferases essential for the initiation of de novo DNA methylation, abolished the establishment of DNA methylation and the silencing of Rhox cluster genes in the embryo proper. The Dnmt3-dependent CpG-island methylation at the Rhox locus extended for a large genomic region (similar to 1 Mb) containing the Rhox cluster and surrounding genes. Complementation experiments using embryonic stem (ES) cells deficient in the DNA methyltransferases suggested that the CpG-island methylation by Dnmt3a and Dnmt3b was restricted within this large genomic region, and did not affect the neighboring genes outside it, implicating the existence of region-specific boundaries. Our results suggest that DNA methylation plays important roles in both long-range gene silencing and lineage-specific silencing in embryogenesis.