A quantitative atlas of histone modification signatures from human cancer cells
A quantitative atlas of histone modification signatures from human cancer cells
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DOI：
10.1186/1756-8935-6-20
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发表时间：
2013-07-05
影响因子：
3.9
通讯作者：
Garcia, Benjamin A.
中科院分区：
文献类型：
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作者：
LeRoy, Gary;DiMaggio, Peter A.;Garcia, Benjamin A.
背景：癌症生物学的一个组成部分是了解独特区分一种癌症类型与另一种癌症类型的分子特性。其中一类特性是组蛋白翻译后修饰 (PTM)。许多组蛋白 PTM 与癌症发展中涉及的相同不同核功能有关，包括转录激活和表观遗传调控，这些功能通常通过标准基因组技术进行间接分析。因此，需要对癌细胞系进行全面、定量的分析，重点关注其染色质修饰状态。结果：为了补充癌细胞系的基因组表达谱，我们通过量化一大组单一和组合组蛋白 H3 和 H4 PTM 以及组蛋白变体的丰度，报告了 24 个不同细胞系（其中大多数是癌细胞）的蛋白质组学分类。在蛋白质组分析的同时，我们对组蛋白修饰酶丰度进行了转录组分析，作为量化其活性水平的代理。虽然转录组学和蛋白质组学结果在根据酶丰度预测组蛋白 PTM 丰度方面总体一致，但一些 PTM 的调节独立于修饰酶的表达。此外，含有 H3K27 甲基化的组合 PTM 在乳腺细胞系中尤其丰富。在小鼠乳腺异种移植模型中，敲除主要的 H3K27 甲基转移酶（zeste 2 增强子 (EZH2)）显着降低了这些动物的肿瘤负荷，并证明了蛋白质组学技术的预测效用。结论：我们对组蛋白修饰状态的蛋白质组学和基因组特征为未来研究表观遗传和非表观遗传提供了资源。 分类和分析癌细胞的决定因素。
Background: An integral component of cancer biology is the understanding of molecular properties uniquely distinguishing one cancer type from another. One class of such properties is histone post-translational modifications (PTMs). Many histone PTMs are linked to the same diverse nuclear functions implicated in cancer development, including transcriptional activation and epigenetic regulation, which are often indirectly assayed with standard genomic technologies. Thus, there is a need for a comprehensive and quantitative profiling of cancer lines focused on their chromatin modification states.Results: To complement genomic expression profiles of cancer lines, we report the proteomic classification of 24 different lines, the majority of which are cancer cells, by quantifying the abundances of a large panel of single and combinatorial histone H3 and H4 PTMs, and histone variants. Concurrent to the proteomic analysis, we performed transcriptomic analysis on histone modifying enzyme abundances as a proxy for quantifying their activity levels. While the transcriptomic and proteomic results were generally consistent in terms of predicting histone PTM abundance from enzyme abundances, several PTMs were regulated independently of the modifying enzyme expression. In addition, combinatorial PTMs containing H3K27 methylation were especially enriched in breast cell lines. Knockdown of the predominant H3K27 methyltransferase, enhancer of zeste 2 (EZH2), in a mouse mammary xenograft model significantly reduced tumor burden in these animals and demonstrated the predictive utility of proteomic techniques.Conclusions: Our proteomic and genomic characterizations of the histone modification states provide a resource for future investigations of the epigenetic and non-epigenetic determinants for classifying and analyzing cancer cells.