Circular ecDNA promotes accessible chromatin and high oncogene expression.
Document Type
Article
Publication Date
11-28-2019
Keywords
JGM
JAX Source
Nature 2019 Nov 28; 575(7784):699-703
Volume
575
Issue
7784
First Page
699
Last Page
703
ISSN
1476-4687
PMID
31748743
DOI
https://doi.org/10.1038/s41586-019-1763-5
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.
Recommended Citation
Wu S,
Turner K,
Nguyen N,
Raviram R,
Erb M,
Santini J,
Luebeck J,
Rajkumar U,
Diao Y,
Li B,
Zhang W,
Jameson N,
Corces M,
Granja J,
Chen X,
Coruh C,
Abnousi A,
Houston J,
Ye Z,
Hu R,
Yu M,
Kim H,
Law J,
Verhaak R,
Hu M,
Furnari F,
Chang H,
Ren B,
Bafna V,
Mischel P.
Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 2019 Nov 28; 575(7784):699-703