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ecDNA hubs drive cooperative intermolecular oncogene expression

Author

Listed:
  • King L. Hung

    (Stanford University School of Medicine)

  • Kathryn E. Yost

    (Stanford University School of Medicine)

  • Liangqi Xie

    (Howard Hughes Medical Institute
    University of California, Berkeley
    Howard Hughes Medical Institute)

  • Quanming Shi

    (Stanford University School of Medicine)

  • Konstantin Helmsauer

    (Charité—Universitätsmedizin Berlin)

  • Jens Luebeck

    (University of California, San Diego
    University of California, San Diego)

  • Robert Schöpflin

    (Max Planck Institute for Molecular Genetics
    Charité—Universitätsmedizin Berlin
    Max Planck Institute for Molecular Genetics)

  • Joshua T. Lange

    (University of California, San Diego
    Stanford University
    Stanford University)

  • Rocío Chamorro González

    (Charité—Universitätsmedizin Berlin)

  • Natasha E. Weiser

    (Stanford University School of Medicine
    Stanford University)

  • Celine Chen

    (Charité—Universitätsmedizin Berlin)

  • Maria E. Valieva

    (Max Planck Institute for Molecular Genetics
    Charité—Universitätsmedizin Berlin)

  • Ivy Tsz-Lo Wong

    (Stanford University
    Stanford University)

  • Sihan Wu

    (University of Texas Southwestern Medical Center)

  • Siavash R. Dehkordi

    (University of California, San Diego)

  • Connor V. Duffy

    (Stanford University School of Medicine)

  • Katerina Kraft

    (Stanford University School of Medicine)

  • Jun Tang

    (Stanford University
    Stanford University)

  • Julia A. Belk

    (Stanford University
    Stanford University)

  • John C. Rose

    (Stanford University School of Medicine)

  • M. Ryan Corces

    (Stanford University School of Medicine)

  • Jeffrey M. Granja

    (Stanford University School of Medicine)

  • Rui Li

    (Stanford University School of Medicine)

  • Utkrisht Rajkumar

    (University of California, San Diego)

  • Jordan Friedlein

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Anindya Bagchi

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Ansuman T. Satpathy

    (Stanford University)

  • Robert Tjian

    (University of California, Berkeley
    Howard Hughes Medical Institute)

  • Stefan Mundlos

    (Max Planck Institute for Molecular Genetics
    Charité—Universitätsmedizin Berlin
    Charité—Universitätsmedizin Berlin)

  • Vineet Bafna

    (University of California, San Diego)

  • Anton G. Henssen

    (Charité—Universitätsmedizin Berlin
    Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
    German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center DKFZ
    Berlin Institute of Health)

  • Paul S. Mischel

    (Stanford University
    Stanford University)

  • Zhe Liu

    (Howard Hughes Medical Institute)

  • Howard Y. Chang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs—clusters of around 10–100 ecDNAs within the nucleus—enable intermolecular enhancer–gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer–gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

Suggested Citation

  • King L. Hung & Kathryn E. Yost & Liangqi Xie & Quanming Shi & Konstantin Helmsauer & Jens Luebeck & Robert Schöpflin & Joshua T. Lange & Rocío Chamorro González & Natasha E. Weiser & Celine Chen & Mar, 2021. "ecDNA hubs drive cooperative intermolecular oncogene expression," Nature, Nature, vol. 600(7890), pages 731-736, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7890:d:10.1038_s41586-021-04116-8
    DOI: 10.1038/s41586-021-04116-8
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    Citations

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    Cited by:

    1. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study," IJERPH, MDPI, vol. 19(18), pages 1-51, September.
    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. 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.
    6. 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.
    7. 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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