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; Paul S. Mischel

doi:10.1038/s41586-019-1763-5

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 HuMiao Yu, Hoon Kim, Julie A. Law, Roel G.W. Verhaak, Ming Hu, Frank B. Furnari, Howard Y. Chang, Bing Ren, Vineet Bafna, Paul S. Mischel

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Abstract

Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer^1,2, 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.

Original language	English (US)
Pages (from-to)	699-703
Number of pages	5
Journal	Nature
Volume	575
Issue number	7784
DOIs	https://doi.org/10.1038/s41586-019-1763-5
State	Published - Nov 28 2019
Externally published	Yes

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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., ... Mischel, P. S. (2019). Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature, 575(7784), 699-703. https://doi.org/10.1038/s41586-019-1763-5

Wu, S, Turner, KM, Nguyen, N, Raviram, R, Erb, M, Santini, J, Luebeck, J, Rajkumar, U, Diao, Y, Li, B, Zhang, W, Jameson, N, Corces, MR, Granja, JM, Chen, X, Coruh, C, Abnousi, A, Houston, J, Ye, Z, Hu, R, Yu, M, Kim, H, Law, JA, Verhaak, RGW, Hu, M, Furnari, FB, Chang, HY, Ren, B, Bafna, V & Mischel, PS 2019, 'Circular ecDNA promotes accessible chromatin and high oncogene expression', Nature, vol. 575, no. 7784, pp. 699-703. https://doi.org/10.1038/s41586-019-1763-5

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title = "Circular ecDNA promotes accessible chromatin and high oncogene expression",

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.",

author = "Sihan Wu and Turner, {Kristen M.} and Nam Nguyen and Ramya Raviram and Marcella Erb and Jennifer Santini and Jens Luebeck and Utkrisht Rajkumar and Yarui Diao and Bin Li and Wenjing Zhang and Nathan Jameson and Corces, {M. Ryan} and Granja, {Jeffrey M.} and Xingqi Chen and Ceyda Coruh and Armen Abnousi and Jack Houston and Zhen Ye and Rong Hu and Miao Yu and Hoon Kim and Law, {Julie A.} and Verhaak, {Roel G.W.} and Ming Hu and Furnari, {Frank B.} and Chang, {Howard Y.} and Bing Ren and Vineet Bafna and Mischel, {Paul S.}",

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AU - Luebeck, Jens

AU - Rajkumar, Utkrisht

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AU - Abnousi, Armen

AU - Houston, Jack

AU - Ye, Zhen

AU - Hu, Rong

AU - Yu, Miao

AU - Kim, Hoon

AU - Law, Julie A.

AU - Verhaak, Roel G.W.

AU - Hu, Ming

AU - Furnari, Frank B.

AU - Chang, Howard Y.

AU - Ren, Bing

AU - Bafna, Vineet

AU - Mischel, Paul S.

PY - 2019/11/28

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N2 - 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.

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Circular ecDNA promotes accessible chromatin and high oncogene expression

Abstract

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