Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells.
Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells.
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DOI：
10.1158/0008-5472.can-17-1724
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发表时间：
2018-05-15
期刊：
影响因子：
11.2
通讯作者：
Iyer VR
中科院分区：
文献类型：
--
作者：
Hall AW;Battenhouse AM;Shivram H;Morris AR;Cowperthwaite MC;Shpak M;Iyer VR
多形性胶质母细胞瘤（GBM）可以通过基因表达分为四个与预后和生存相关的主要亚型，但增强子和其他基因调控元件尚未在原发性肿瘤中确定。在这里，我们分析了原发性胶质瘤中的六种组蛋白修饰和CTCF结合以及基因表达，并确定了在肿瘤基因组中定义不同调控元件的染色质状态。间充质和经典肿瘤亚型中的增强子驱动与细胞迁移和侵袭相关的基因表达，而前神经肿瘤中的增强子控制与GBM中侵袭性较低的表型相关的基因。我们确定了二价结构域标记的激活和抑制染色质修饰。有趣的是，从共同的（亚型独立的）二价结构域的基因相互作用网络是高度富集的同源盒基因和转录因子，并占主导地位的SHH和Wnt信号通路。这种早期神经发育的亚型独立特征可能表明胶质母细胞瘤中的去分化能力，并可能提供潜在的治疗靶点。
Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and CTCF binding as well as gene expression in primary gliomas, and identified chromatin states that define distinct regulatory elements across the tumor genome. Enhancers in mesenchymal and classical tumor subtypes drove gene expression associated with cell migration and invasion, while enhancers in proneural tumors controlled genes associated with a less aggressive phenotype in GBM. We identified bivalent domains marked by activating and repressive chromatin modifications. Interestingly, the gene interaction network from common (subtype-independent) bivalent domains was highly enriched for homeobox genes and transcription factors, and dominated by SHH and Wnt signaling pathways. This subtype-independent signature of early neural development may be indicative of poised de-differentiation capacity in glioblastoma, and could provide potential targets for therapy.