Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.
Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.
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DOI：
10.1126/science.1255104
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发表时间：
2014-08-29
期刊：
影响因子：
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通讯作者：
Shilatifard A
中科院分区：
文献类型：
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作者：
Herz HM;Morgan M;Gao X;Jackson J;Rickels R;Swanson SK;Florens L;Washburn MP;Eissenberg JC;Shilatifard A
组蛋白 H3 赖氨酸 27 至蛋氨酸 (H3K27M) 功能获得突变发生在高度侵袭性的儿童神经胶质瘤中。在这里，我们建立了致病性组蛋白 H3K27M 突变的果蝇动物模型，并表明其过度表达类似于 Polycomb 抑制复合物 2 (PRC2) 功能丧失表型，导致 PRC2 靶基因的去抑制和发育扰动。类似地，H3K9M 突变体会消耗 H3K9 甲基化水平并抑制各种果蝇组织中的位置效应杂色。组蛋白 H3K9 去甲基化酶 KDM3B/JHDM2 与 H3K9M 核小体相关，其在果蝇中的过度表达会导致 H3K9 甲基化水平丧失和异染色质沉默缺陷。在这里，我们建立了组蛋白赖氨酸到蛋氨酸突变体作为抑制甲基化途径的强大体内工具，也可作为捕获位点特异性组蛋白修饰酶的生化试剂，从而提供对染色质信号传导途径的分子洞察。
Histone H3 lysine27-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. Here, we establish a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles Polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing de-repression of PRC2 target genes and developmental perturbations. Similarly, a H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M nucleosomes and its overexpression in Drosophila results in loss of H3K9 methylation levels and heterochromatic silencing defects. Here we establish histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin-signaling pathways.