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Circular ecDNA promotes accessible chromatin and high oncogene expression

Author

Listed:
  • Sihan Wu

    (University of California at San Diego)

  • Kristen M. Turner

    (University of California at San Diego
    Boundless Bio, Inc.)

  • Nam Nguyen

    (University of California at San Diego
    Boundless Bio, Inc.)

  • 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
    Duke University School of Medicine
    Duke University School of Medicine)

  • 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
    Uppsala 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
    Stanford University)

  • Bing Ren

    (University of California at San Diego
    University of California at San Diego
    University of California at San Diego)

  • Vineet Bafna

    (University of California at San Diego)

  • Paul S. Mischel

    (University of California at San Diego
    University of California at San Diego
    University of California at San Diego)

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.

Suggested Citation

  • 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 &, 2019. "Circular ecDNA promotes accessible chromatin and high oncogene expression," Nature, Nature, vol. 575(7784), pages 699-703, November.
    • Handle: RePEc:nat:nature:v:575:y:2019:i:7784:d:10.1038_s41586-019-1763-5
    DOI: 10.1038/s41586-019-1763-5
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    Cited by:

    1. Alvin Wei Tian Ng & Dylan Peter McClurg & Ben Wesley & Shahriar A. Zamani & Emily Black & Ahmad Miremadi & Olivier Giger & Rogier ten Hoopen & Ginny Devonshire & Aisling M. Redmond & Nicola Grehan & S, 2024. "Disentangling oncogenic amplicons in esophageal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Qionghua Zhu & Xin Zhao & Yuanhang Zhang & Yanping Li & Shang Liu & Jingxuan Han & Zhiyuan Sun & Chunqing Wang & Daqi Deng & Shanshan Wang & Yisen Tang & Yaling Huang & Siyuan Jiang & Chi Tian & Xi Ch, 2023. "Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Jinxin Phaedo Chen & Constantin Diekmann & Honggui Wu & Chong Chen & Giulia Chiara & Enrico Berrino & Konstantinos L. Georgiadis & Britta A. M. Bouwman & Mohit Virdi & Luuk Harbers & Sara Erika Bellom, 2024. "scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Jundong Zhuang & Yaoxin Zhang & Congcong Zhou & Danlin Fan & Tao Huang & Qi Feng & Yiqi Lu & Yan Zhao & Qiang Zhao & Bin Han & Tingting Lu, 2024. "Dynamics of extrachromosomal circular DNA in rice," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Xue-Ke Zhao & Pengwei Xing & Xin Song & Miao Zhao & Linxuan Zhao & Yonglong Dang & Ling-Ling Lei & Rui-Hua Xu & Wen-Li Han & Pan-Pan Wang & Miao-Miao Yang & Jing-Feng Hu & Kan Zhong & Fu-You Zhou & Xu, 2021. "Focal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    7. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    8. Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Akshaya Ramakrishnan & Aikaterini Symeonidi & Patrick Hanel & Katharina T. Schmid & Maria L. Richter & Michael Schubert & Maria Colomé-Tatché, 2023. "epiAneufinder identifies copy number alterations from single-cell ATAC-seq data," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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