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

Nature. 2019 Nov;575(7784):699-703. doi: 10.1038/s41586-019-1763-5. Epub 2019 Nov 20.

Authors

Sihan Wu^#¹, Kristen M Turner^#^{1

2}, Nam Nguyen^#^{3

2}, Ramya Raviram¹, Marcella Erb⁴, Jennifer Santini⁴, Jens Luebeck⁵, Utkrisht Rajkumar³, Yarui Diao^{1

6

7}, Bin Li¹, Wenjing Zhang¹, Nathan Jameson¹, M Ryan Corces⁸, Jeffrey M Granja⁸, Xingqi Chen^{8

9}, Ceyda Coruh¹⁰, Armen Abnousi¹¹, Jack Houston¹, Zhen Ye¹, Rong Hu¹, Miao Yu¹, Hoon Kim¹², Julie A Law¹⁰, Roel G W Verhaak¹², Ming Hu¹¹, Frank B Furnari¹, Howard Y Chang^{13

14}, Bing Ren^{15

16

17}, Vineet Bafna¹⁸, Paul S Mischel^{19

20

21}

Affiliations

¹ Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
² Boundless Bio, Inc., La Jolla, CA, USA.
³ Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA.
⁴ UCSD Light Microscopy Core Facility, Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA.
⁵ Bioinformatics & Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA.
⁶ Department of Cell Biology, Regeneration Next Initiative, Duke University School of Medicine, Durham, NC, USA.
⁷ Department of Orthopaedic Surgery, Regeneration Next Initiative, Duke University School of Medicine, Durham, NC, USA.
⁸ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
⁹ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
¹⁰ Plant Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
¹¹ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
¹³ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. howchang@stanford.edu.
¹⁴ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. howchang@stanford.edu.
¹⁵ Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA. biren@ucsd.edu.
¹⁶ Department of Cellular and Molecular Medicine, Center for Epigenomics, University of California at San Diego, La Jolla, CA, USA. biren@ucsd.edu.
¹⁷ Institute of Genomic Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA. biren@ucsd.edu.
¹⁸ Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, USA. vbafna@cs.ucsd.edu.
¹⁹ Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA. pmischel@ucsd.edu.
²⁰ Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA. pmischel@ucsd.edu.
²¹ Department of Pathology, University of California at San Diego, La Jolla, CA, USA. pmischel@ucsd.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Chromatin / chemistry
Chromatin / genetics*
DNA, Circular / genetics
DNA, Circular / metabolism*
Gene Expression Regulation, Neoplastic / genetics*
Humans
Microscopy, Electron, Scanning
Neoplasms / genetics*
Neoplasms / physiopathology
Oncogenes / genetics*

Substances

Chromatin
DNA, Circular

Abstract

Publication types

MeSH terms

Substances

Grants and funding