Functional Enhancers Shape Extrachromosomal Oncogene Amplifications

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-ampli...

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Vydáno v:	Cell Ročník 179; číslo 6; s. 1330
Hlavní autoři:	Morton, Andrew R, Dogan-Artun, Nergiz, Faber, Zachary J, MacLeod, Graham, Bartels, Cynthia F, Piazza, Megan S, Allan, Kevin C, Mack, Stephen C, Wang, Xiuxing, Gimple, Ryan C, Wu, Qiulian, Rubin, Brian P, Shetty, Shashirekha, Angers, Stephane, Dirks, Peter B, Sallari, Richard C, Lupien, Mathieu, Rich, Jeremy N, Scacheri, Peter C
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 27.11.2019
Témata:	Acetylation Cell Line, Tumor Cell Survival - genetics Chromatin - metabolism Chromosomes, Human - genetics CRISPR-Cas Systems - genetics DNA, Neoplasm - genetics Enhancer Elements, Genetic ErbB Receptors - genetics ErbB Receptors - metabolism Gene Amplification Genes, Neoplasm Genetic Loci Glioblastoma - genetics Glioblastoma - pathology Histones - metabolism Humans Neuroglia - metabolism Oncogenes enhancer MYCN double minute glioblastoma epigenetic MYC oncogene amplification extrachromosomal DNA EGFR
ISSN:	1097-4172, 1097-4172
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2019.10.039