Reading between the Lines: "ADD"-ing Histone and DNA Methylation Marks toward a New Epigenetic "Sum".
Reading between the Lines: "ADD"-ing Histone and DNA Methylation Marks toward a New Epigenetic "Sum".
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DOI：
10.1021/acschembio.5b00830
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发表时间：
2016-03-18
影响因子：
4
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Noh KM;Allis CD;Li H
两种DNA组蛋白的共价修饰共同定义了我们表观基因组的景观。在这篇综述中，我们探讨组蛋白和DNA修饰之间的相互联系，专注于一个保守的染色质结合的调节结构域，ATRX-DNMT 3-DNMT 3L（ADD）域。新的研究表明，ADD结构域能够感知并因此整合多种组蛋白修饰的状态。这又决定了全长含ADD蛋白的体内定位或变构调节及其在下游染色质重塑事件中发挥作用的能力。重新设计从头DNA甲基转移酶DNMT 3A中的ADD“读取器口袋”以使其将该“写入器”重定向至新的基因组基因座的策略证明可用于理解通过改变组蛋白标记的阅读而错误靶向DNA甲基化的重要生物下游后果。与基因组编辑工具相结合，这种方法作为一种原则性的方法，将广泛适用于阐明被“阅读器”突变改变的表观遗传网络，无论是人工还是自然发生在一些人类疾病中。
Covalent modifications of both DNA histones act in concert to define the landscape of our epigenome. In this review, we explore the interconnections between histone and DNA modifications by focusing on a conserved chromatin-binding regulatory domain, the ATRX-DNMT3-DNMT3L (ADD) domain. New studies show that the ADD domain is capable of sensing, and therefore integrating, the status of multiple histone modifications. This in turn dictates the in vivo localization or allosteric regulation of the full-length ADD-containing protein and its ability to function in downstream chromatin remodeling events. Strategies to re-engineer the ADD “reader pocket” in the de novo DNA methyltransferase DNMT3A such that it redirects this “writer” to new genomic loci proved useful in understanding important biological downstream consequences of mis-targeting of DNA methylation via altered reading of histone marks. Combined with genome-editing tools, this approach stands as a poof-of-principle and will be broadly applicable to the elucidation of epigenetic networks that have been altered by “reader” mutations, either artificially or as naturally occurs in some human diseases.