MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin
MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin
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DOI：
10.1016/j.ccell.2015.10.005
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发表时间：
2015-12-14
期刊：
影响因子：
50.3
通讯作者：
Dirks, Peter B.
中科院分区：
文献类型：
--
作者：
Gallo, Marco;Coutinho, Fiona J.;Dirks, Peter B.
三分之一的儿童胶质母细胞瘤 (GBM) 中发现了组蛋白 3 变体 H3.3 突变，但成人肿瘤中并未发现。在这里，我们证明 H3.3 是成人 GBM 功能特性的动态决定因素。 H3.3 在自我更新的 GBM 细胞中受到混合谱系白血病 5 (MLL5) 的抑制。 MLL5 是一种全局表观遗传抑制因子，通过在染色体上插入致密染色质焦点来协调染色质结构的重组，从而有利于致瘤和自我更新特性。相反，H3.3 拮抗自我更新并促进分化。我们利用这些表观遗传状态合理地识别了两种在临床前模型中有效抑制癌症干细胞特性的小分子。我们的工作揭示了 MLL5 和 H3.3 在维持成人 GBM 自我更新层次结构中的作用。
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.