Global analysis of functional relationships between histone point mutations and the effects of histone deacetylase inhibitors
Global analysis of functional relationships between histone point mutations and the effects of histone deacetylase inhibitors
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DOI：
10.1111/j.1365-2443.2010.01408.x
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发表时间：
2010-06
期刊：
影响因子：
2.1
通讯作者：
L. Sato;Shuhei Noguchi;Y. Hayashi;M. Sakamoto;M. Horikoshi
中科院分区：
文献类型：
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作者：
L. Sato;Shuhei Noguchi;Y. Hayashi;M. Sakamoto;M. Horikoshi
以往研究对组蛋白-GLibrary的综合分析表明，大多数组蛋白核心区修饰位点的突变体表现出表型，而组蛋白N末端非结构化尾区（N-tails）修饰的突变体则没有。一个可能的原因是 N 尾的修饰相互连接，形成一个无标度网络，称为组蛋白“修饰网”。在网络中，创建补偿路径以获得针对任何缺陷的鲁棒性。由于这种稳健性，很难确定体内 N 尾中单个组蛋白修饰的重要性。为了克服这个问题，我们采用了药物协同抑制修饰酶的策略，并观察了补偿途径很大程度上中断时的突变表型。我们使用组蛋白脱乙酰酶 (HDAC) 抑制剂分析组蛋白-GLibrary，并鉴定出新的表型突变体。我们还通过联合使用 HDAC 抑制剂和 DNA 介导反应抑制剂来检查表型变化。组蛋白 N 尾中可修饰位点 H3-K4 和 H4-K16 的突变（被认为是网络的“枢纽”）导致了可识别的表型。获得的数据为推测 N 尾组蛋白修饰与生物功能之间的新关系以及预测核心组蛋白中未知的修饰位点提供了有价值的信息。
Comprehensive analyses of the histone‐GLibrary in previous studies showed that most mutants of modification sites in the histone core regions show phenotypes, whereas those with modifications in the histone N‐terminal unstructured tail regions (N‐tails) do not. One possible reason is that modifications in N‐tails are linked to each other to form a scale‐free network termed histone ‘modification web’. In the network, the compensatory pathways are created to acquire the robustness against the any defects. Because of this robustness, it is difficult to determine the significance of the individual histone modifications in N‐tails in vivo. To overcome this problem, we used a strategy using drugs coordinately to inhibit modification enzymes and observed the mutant phenotypes when the compensatory pathways are largely interrupted. We analyzed histone‐GLibrary using inhibitors of histone deacetylases (HDACs) and identified novel phenotypic mutants. We also examined the phenotypic changes through the combined use of an HDAC inhibitor and an inhibitor of DNA‐mediated reactions. Mutation of modifiable sites H3‐K4 and H4‐K16 in histone N‐tails, which are presumed to be the ‘hubs’ of the network, resulted in identifiable phenotypes. The data obtained provide valuable information for speculation on novel relationships between histone modification in N‐tails and biological function and for predicting unknown modification sites in core histones.