Circular ecDNA promotes accessible chromatin and high oncogene expression

Sihan Wu, Kristen M. Turner, Nam Nguyen, Ramya Raviram, Marcella Erb, Jennifer Santini, Jens Luebeck, Utkrisht Rajkumar, Yarui Diao, Bin Li, Wenjing Zhang, Nathan Jameson, M. Ryan Corces, Jeffrey M. Granja, Xingqi Chen, Ceyda Coruh, Armen Abnousi, Jack Houston, Zhen Ye, Rong Hu, Miao Yu, Hoon Kim, Julie A. Law, Roel G. W. Verhaak, Ming Hu, Frank B. Furnari, Howard Y. Chang (), Bing Ren (), Vineet Bafna () and Paul S. Mischel ()
Additional contact information
Sihan Wu: University of California at San Diego
Kristen M. Turner: University of California at San Diego
Nam Nguyen: University of California at San Diego
Ramya Raviram: University of California at San Diego
Marcella Erb: University of California at San Diego
Jennifer Santini: University of California at San Diego
Jens Luebeck: University of California at San Diego
Utkrisht Rajkumar: University of California at San Diego
Yarui Diao: University of California at San Diego
Bin Li: University of California at San Diego
Wenjing Zhang: University of California at San Diego
Nathan Jameson: University of California at San Diego
M. Ryan Corces: Stanford University
Jeffrey M. Granja: Stanford University
Xingqi Chen: Stanford University
Ceyda Coruh: Salk Institute for Biological Studies
Armen Abnousi: Lerner Research Institute, Cleveland Clinic Foundation
Jack Houston: University of California at San Diego
Zhen Ye: University of California at San Diego
Rong Hu: University of California at San Diego
Miao Yu: University of California at San Diego
Hoon Kim: The Jackson Laboratory for Genomic Medicine
Julie A. Law: Salk Institute for Biological Studies
Roel G. W. Verhaak: The Jackson Laboratory for Genomic Medicine
Ming Hu: Lerner Research Institute, Cleveland Clinic Foundation
Frank B. Furnari: University of California at San Diego
Howard Y. Chang: Stanford University
Bing Ren: University of California at San Diego
Vineet Bafna: University of California at San Diego
Paul S. Mischel: University of California at San Diego

Nature, 2019, vol. 575, issue 7784, 699-703

Abstract: Abstract Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

Date: 2019
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DOI: 10.1038/s41586-019-1763-5

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