Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation
Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation
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DOI：
10.1038/74191
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发表时间：
2000-04-01
期刊：
影响因子：
30.8
通讯作者：
Higgs, DR
中科院分区：
文献类型：
--
作者：
Gibbons, RJ;McDowell, TL;Higgs, DR
分子遗传学的一个目标是了解基本核过程、表观遗传变化和协调这些影响的众多蛋白质之间的关系。其中一种蛋白ATRX含有一个高度保守的植物同源结构域（PHD）样结构域，存在于许多染色质相关蛋白中，以及一个羧基末端结构域，该结构域将其识别为解旋酶/ atp酶SNF2家族的成员（1,2）。ATRX基因突变可导致特征性发育异常，包括严重智力迟钝、面部畸形、泌尿生殖系统异常和α -地中海贫血(1)。这一间接证据表明，ATRX可能通过对染色质的影响而发挥转录调节作用。我们最近发现，在间期和有丝分裂过程中，ATRX定位于中心周围异染色质，这表明ATRX可能在细胞核中发挥染色质介导的其他作用。此外，在中期，一些ATRX定位于或接近人类单中心染色体短臂上的核糖体DNA （rDNA）阵列(3)。在这里，我们发现ATRX的突变引起了几个高度重复序列的甲基化模式的变化，包括rDNA阵列、y特异性卫星和亚端粒重复序列。我们的发现提供了哺乳动物发育中染色质重塑、DNA甲基化和基因表达过程之间的潜在联系。
A goal of molecular genetics is to understand the relationship between basic nuclear processes, epigenetic changes and the numerous proteins that orchestrate these effects. One such protein, ATRX, contains a highly conserved plant homeodomain (PHD)-like domain, present in many chromatin-associated proteins, and a carboxy-terminal domain which identifies it as a member of the SNF2 family of helicase/ATPases(1,2). Mutations in ATRX give rise to characteristic developmental abnormalities including severe mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassaemia(1). This circumstantial evidence suggests that ATRX may act as a transcriptional regulator through an effect on chromatin. We have recently shown that ATRX is localized to pericentromeric heterochromatin during interphase and mitosis, suggesting that ATRX might exert other chromatin-mediated effects in the nucleus. Moreover, at metaphase, some ATRX is localized at or close to the ribosomal DNA (rDNA) arrays on the short arms of human acrocentric chromosomes(3). Here we show that mutations in ATRX give rise to changes in the pattern of methylation of several highly repeated sequences including the rDNA arrays, a Y-specific satellite and subtelomeric repeats. Our findings provide a potential link between the processes of chromatin remodelling, DNA methylation and gene expression in mammalian development.