Functional Enhancers Shape Extrachromosomal Oncogene Amplifications
Functional Enhancers Shape Extrachromosomal Oncogene Amplifications
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DOI：
10.1016/j.cell.2019.10.039
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发表时间：
2019-11-27
期刊：
影响因子：
64.5
通讯作者：
Scacheri, Peter C.
中科院分区：
文献类型：
--
作者：
Morton, Andrew R.;Dogan-Artun, Nergiz;Scacheri, Peter C.
超出癌基因边界的非编码区域在很大程度上被忽略了。使用计算方法，我们发现非编码 DNA 的显着共扩增特征超出了五种癌症类型中扩增癌基因的界限。在胶质母细胞瘤中，EGFR 优先与其在原始细胞类型中活跃的两种内源性增强子元件共同扩增。这些调控元件、它们的接触以及它们对细胞健康的贡献都被保留在高水平的环状染色体外 DNA 扩增中。使用 CRISPR 干扰筛选方法询问基因座，揭示了影响细胞健康的多种其他元素。适应性依赖性的模式反映了调节元件的重新排列以及染色体外扩增子上染色质拓扑结构的重新布线。我们的研究表明，癌基因扩增是由非编码基因组中的调控依赖性决定的。
Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.