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EcDNA hubs drive cooperative intermolecular oncogene expression

View ORCID ProfileKing L. Hung, View ORCID ProfileKathryn E. Yost, Liangqi Xie, Sihan Wu, Joshua T. Lange, Connor V. Duffy, View ORCID ProfileKaterina Kraft, Jun Tang, Quanming Shi, John C. Rose, M. Ryan Corces, Jeffrey M. Granja, Rui Li, Utkrisht Rajkumar, Robert Tjian, Vineet Bafna, Paul S. Mischel, Zhe Liu, Howard Y. Chang
doi: https://doi.org/10.1101/2020.11.19.390278
King L. Hung
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • ORCID record for King L. Hung
Kathryn E. Yost
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Liangqi Xie
2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
3Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley, CA, USA
4Howard Hughes Medical Institute, Berkeley, CA, USA
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Sihan Wu
5Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
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Joshua T. Lange
5Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
6Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA, 92093, USA
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Connor V. Duffy
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Katerina Kraft
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • ORCID record for Katerina Kraft
Jun Tang
5Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
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Quanming Shi
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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John C. Rose
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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M. Ryan Corces
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Jeffrey M. Granja
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Rui Li
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
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Utkrisht Rajkumar
7Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA
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Robert Tjian
3Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley, CA, USA
4Howard Hughes Medical Institute, Berkeley, CA, USA
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Vineet Bafna
7Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA
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Paul S. Mischel
5Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA
8Department of Pathology, University of California at San Diego, La Jolla, CA, USA
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Zhe Liu
2Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
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Howard Y. Chang
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA
9Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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  • For correspondence: howchang@stanford.edu
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ABSTRACT

Extrachromosomal DNAs (ecDNAs) are prevalent in human cancers and mediate high oncogene expression through elevated copy number and altered gene regulation1. Gene expression typically involves distal enhancer DNA elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs, comprised of ~10-100 ecDNAs clustered in the nucleus of interphase cells, drive intermolecular enhancer input for amplified oncogene expression. Single-molecule sequencing, single-cell multiome, and 3D enhancer connectome reveal subspecies of MYC-PVT1 ecDNAs lacking enhancers that access intermolecular and ectopic enhancer-promoter interactions in ecDNA hubs. ecDNA hubs persist without transcription and are tethered by BET protein BRD4. BET inhibitor JQ1 disperses ecDNA hubs, preferentially inhibits ecDNA oncogene transcription, and kills ecDNA+ cancer cells. Two amplified oncogenes MYC and FGFR2 intermix in ecDNA hubs, engage in intermolecular enhancer-promoter interactions, and transcription is uniformly sensitive to JQ1. Thus, ecDNA hubs are nuclear bodies of many ecDNAs tethered by proteins and platforms for cooperative transcription, leveraging the power of oncogene diversification and combinatorial DNA interactions. We suggest ecDNA hubs, rather than individual ecDNAs, as units of oncogene function, cooperative evolution, and new targets for cancer therapy.

Competing Interest Statement

H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and an advisor of 10x Genomics, Arsenal Biosciences, and Spring Discovery. P.S.M. is a co-founder of Boundless Bio, Inc. He has equity and chairs the scientific advisory board, for which he is compensated. V.B. is a co-founder and advisor of Boundless Bio.

Footnotes

  • ↵# These authors share co-first authorship

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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EcDNA hubs drive cooperative intermolecular oncogene expression
King L. Hung, Kathryn E. Yost, Liangqi Xie, Sihan Wu, Joshua T. Lange, Connor V. Duffy, Katerina Kraft, Jun Tang, Quanming Shi, John C. Rose, M. Ryan Corces, Jeffrey M. Granja, Rui Li, Utkrisht Rajkumar, Robert Tjian, Vineet Bafna, Paul S. Mischel, Zhe Liu, Howard Y. Chang
bioRxiv 2020.11.19.390278; doi: https://doi.org/10.1101/2020.11.19.390278
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EcDNA hubs drive cooperative intermolecular oncogene expression
King L. Hung, Kathryn E. Yost, Liangqi Xie, Sihan Wu, Joshua T. Lange, Connor V. Duffy, Katerina Kraft, Jun Tang, Quanming Shi, John C. Rose, M. Ryan Corces, Jeffrey M. Granja, Rui Li, Utkrisht Rajkumar, Robert Tjian, Vineet Bafna, Paul S. Mischel, Zhe Liu, Howard Y. Chang
bioRxiv 2020.11.19.390278; doi: https://doi.org/10.1101/2020.11.19.390278

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