Functional Enhancers Shape Extrachromosomal Oncogene Amplifications.,Cell

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Functional Enhancers Shape Extrachromosomal Oncogene Amplifications.
Cell ( IF 45.5 ) Pub Date : 2019-11-21 , DOI: 10.1016/j.cell.2019.10.039
Andrew R Morton ₁ , Nergiz Dogan-Artun ₂ , Zachary J Faber ₁ , Graham MacLeod ₃ , Cynthia F Bartels ₁ , Megan S Piazza ₄ , Kevin C Allan ₁ , Stephen C Mack ₅ , Xiuxing Wang ₆ , Ryan C Gimple ₇ , Qiulian Wu ₆ , Brian P Rubin ₈ , Shashirekha Shetty ₄ , Stephane Angers ₉ , Peter B Dirks ₁₀ , Richard C Sallari ₁₁ , Mathieu Lupien ₁₂ , Jeremy N Rich ₁₃ , Peter C Scacheri ₁

Affiliation

Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Center for Human Genetics Laboratory, University Hospitals, Cleveland, OH 44106, USA.
Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA.
Departments of Anatomic Pathology and Molecular Genetics, Cleveland Clinic, Lerner Research Institute and Taussig Cancer Center, Cleveland, OH 44195, USA.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M5G 0A4, Canada.
Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
Axiotl Inc., Tucson, AZ 85701, USA.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA.

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.

中文翻译：

功能增强剂可塑造染色体外致癌基因扩增。

在致癌基因边界之外扩增的非编码区在很大程度上已被忽略。使用一种计算方法，我们发现跨越五种癌症类型的扩增癌基因的边界，非编码DNA的显着共扩增的特征。在胶质母细胞瘤中，EGFR优先与其在来源细胞类型中具有活性的两个内源性增强因子共同扩增。这些调节元件，它们的接触及其对细胞适应性的贡献保留在高水平的环状染色体外DNA扩增中。用CRISPR干扰筛选方法对基因座进行询问，揭示了影响细胞适应性的多种其他因素。适应性依存关系的模式反映了调控元件的重排，并伴随着染色体外扩增子上染色质拓扑的重新布线。

更新日期：2019-11-22

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