Escape from gene silencing in ICF syndrome:: evidence for advanced replication time as a major determinant
Escape from gene silencing in ICF syndrome:: evidence for advanced replication time as a major determinant
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DOI：
10.1093/hmg/9.18.2575
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发表时间：
2000-11-01
影响因子：
3.5
通讯作者：
Gartler, SM
中科院分区：
文献类型：
--
作者：
Hansen, RS;Stöger, R;Gartler, SM
与经典卫星区低甲基化相关的染色体异常是ICF免疫缺陷综合征的特征。我们和其他人发现，这些效应来自DNMT3B DNA甲基转移酶基因的突变。在这里，我们进一步研究了ICF细胞的分子表型，并报告了几个与先进的复制时间，核酸酶超敏性和非活性X和Y染色体上的基因沉默的变量逃逸相关的广泛的低甲基化的例子。我们的分析表明，失活的X染色体上的所有基因可能在其5' CpG岛上极度低甲基化。我们对一名ICF女性中的G6PD和另一名ICF女性中的SYBL 1的研究提供了未转化的人成纤维细胞中X染色体失活的异常逃逸的第一个例子，XIST RNA定位在这些细胞中是正常的，反对这种RNA在体细胞中的独立沉默作用。SYBL1沉默也在ICF雄性细胞中的Y染色体上被破坏。染色质对核酸酶的敏感性增加，发现在所有低甲基化的启动子检查，包括那些沉默的基因，在这些后一种情况下，失活的持久性似乎严重依赖于延迟复制的DNA，因为逃避沉默，只有看到复制时，先进的一个活跃的X样模式。
Chromosomal abnormalities associated with hypomethylation of classical satellite regions are characteristic for the ICF immunodeficiency syndrome. We, as well as others, have found that these effects derive from mutations in the DNMT3B DNA methyltransferase gene. Here we examine further the molecular phenotype of ICF cells and report several examples of extensive hypomethylation that are associated with advanced replication time, nuclease hypersensitivity and a variable escape from silencing for genes on the inactive X and Y chromosomes. Our analysis suggests that all genes on the inactive X chromosome may be extremely hypomethylated at their 5' CpG islands, Our studies of G6PD in one ICF female and SYBL1 in another ICF female provide the first examples of abnormal escape from X chromosome inactivation in untransformed human fibroblasts, XIST RNA localization is normal in these cells, arguing against an independent silencing role for this RNA in somatic cells. SYBL1 silencing is also disrupted on the Y chromosome in ICF male cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes, The persistence of inactivation in these latter cases appears to depend critically on delayed replication of DNA because escape from silencing was only seen when replication was advanced to an active X-like pattern.