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

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)699-703
Number of pages5
JournalNature
Volume575
Issue number7784
DOIs
StatePublished - Nov 28 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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