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Circular ecDNA promotes accessible chromatin and high oncogene expression
Open accessAbstract
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. Imaging and sequencing approaches are combined to show that extrachromosomal DNA (ecDNA) in cancer is circular and has unique chromatin structure that amplifies oncogene output.
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Cites
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Self-citationThe chromatin accessibility landscape of primary human cancers
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Self-citationOrganizational principles of 3D genome architecture
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Self-citationMAPS: Model-based analysis of long-range chromatin interactions from PLAC-seq and HiChIP experiments
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“the minimum fold change range we used from MACC2 is the default [5-50].”
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Metadata
- Authors
- Wu, S., Turner, K. M., Nguyen, N., Raviram, R., Erb, M., Santini, J., Luebeck, J., Rajkumar, U., Diao, Y., Li, B., Zhang, W., Jameson, N., Corces, M. R., Granja, J. M., Chen, X., Coruh, C., Abnousi, A., Houston, J., Ye, Z., Hu, R., Yu, M., Kim, H., Law, J. A., Verhaak, R. G. W., Hu, M., Furnari, F. B., Chang, H. Y., Ren, B., Bafna, V., & Mischel, P. S.
- Venue
- Nature
- Published
- 2019-11-20
- Volume
- 575
- Issue
- 7784
- Pages
- 699-703
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2991552764
- Cited by
- 667
- References
- 8
- FWCI
- 29.93
- Type
- journal article
- Language
- en
- Open access
- green
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