Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin.
Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin.
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DOI：
10.1002/iub.386
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发表时间：
2010-10
期刊：
影响因子：
4.6
通讯作者：
Woodcock, Christopher L.
中科院分区：
文献类型：
--
作者：
Hansen, Jeffrey C.;Ghosh, Rajarshi P.;Woodcock, Christopher L.
关键词：
甲基化 CpG 结合蛋白 2 (MeCP2) 是一种核蛋白，因其选择性识别甲基化 DNA 的能力而得名。人们的注意力集中在了解 MeCP2 的结构和功能及其在 Rett 综合征中的作用，Rett 综合征是一种严重的神经发育障碍，每 10,000-15,000 名女孩中就有一人患有这种疾病。早期研究表明 DNA 甲基化、MeCP2 与特定基因启动子上抑制性染色质结构的建立之间存在联系。然而，现在人们认识到 MeCP2 可以根据具体情况激活和抑制特定基因。同样，在细胞中，除了甲基化 DNA 外，MeCP2 还与未甲基化 DNA 和染色质结合。因此，为了了解 MeCP2 功能的分子基础，有必要阐明 MeCP2 与基因组非甲基化和甲基化区域结合之间复杂的相互关系。 MeCP2 不寻常且有趣，因为它是一种本质上无序的蛋白质，也就是说，其大部分一级序列无法折叠成二级结构，但仍具有功能。 MeCP2 的独特结构是本文第一部分的主题。然后我们讨论了 MeCP2 与非甲基化和甲基化 DNA 体外结合的最新研究，以及这项工作对体内功能的潜在影响。我们最后重点关注机制研究，表明 MeCP2 与染色质的结合导致压缩成局部（二级）和全局（三级）高级结构。 MeCP2 还与组蛋白 H1 竞争核小体结合位点。最近发现 MeCP2 与神经元细胞中的核小体处于接近化学计量水平，这强调了 MeCP2 与基因组结合的多种模式，其中包括甲基化密度的协作跟踪。
Methylated CpG Binding Protein 2 (MeCP2) is a nuclear protein named for its ability to selectively recognize methylated DNA. Much attention has been focused on understanding MeCP2 structure and function in the context of its role in Rett syndrome, a severe neurodevelopmental disorder that afflicts one in 10,000–15,000 girls. Early studies suggested a connection between DNA methylation, MeCP2, and establishment of a repressive chromatin structure at specific gene promoters. However, it is now recognized that MeCP2 can both activate and repress specific genes depending on the context. Likewise, in the cell, MeCP2 is bound to unmethylated DNA and chromatin in addition to methylated DNA. Thus, to understand the molecular basis of MeCP2 functionality, it is necessary to unravel the complex interrelationships between MeCP2 binding to unmethylated and methylated regions of the genome. MeCP2 is unusual and interesting in that it is an intrinsically disordered protein, that is, much of its primary sequence fails to fold into secondary structure and yet is functional. The unique structure of MeCP2 is the subject of the first section of this article. We then discuss recent investigations of the in vitro binding of MeCP2 to unmethylated and methylated DNA, and the potential ramifications of this work for in vivo function. We close by focusing on mechanistic studies indicating that the binding of MeCP2 to chromatin results in compaction into local (secondary) and global (tertiary) higher order structures. MeCP2 also competes with histone H1 for nucleosomal binding sites. The recent finding that MeCP2 is found at near stoichiometric levels with nucleosomes in neuronal cells underscores the multiple modes of engagement of MeCP2 with the genome, which include the cooperative tracking of methylation density.
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