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eccDNAs are apoptotic products with high innate immunostimulatory activity

Author

Listed:
  • Yuangao Wang

    (Howard Hughes Medical Institute
    Boston Children’s Hospital)

  • Meng Wang

    (Howard Hughes Medical Institute
    Boston Children’s Hospital)

  • Mohamed Nadhir Djekidel

    (Howard Hughes Medical Institute
    Boston Children’s Hospital)

  • Huan Chen

    (Howard Hughes Medical Institute
    Boston Children’s Hospital)

  • Di Liu

    (Harvard University
    Harvard Medical School)

  • Frederick W. Alt

    (Howard Hughes Medical Institute
    Boston Children’s Hospital
    Harvard University)

  • Yi Zhang

    (Howard Hughes Medical Institute
    Boston Children’s Hospital
    Harvard University
    Harvard Stem Cell Institute WAB-149G)

Abstract

Extrachromosomal circular DNA elements (eccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species1,2. However, their biogenesis and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs map across the entire genome in a close to random manner, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistent with this idea, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a manner that is independent of eccDNA sequence but dependent on eccDNA circularity and the cytosolic DNA sensor Sting. Collectively, our study not only revealed the origin, biogenesis and immunostimulant function of eccDNAs but also uncovered their sensing pathway and potential clinical implications in immune response.

Suggested Citation

  • Yuangao Wang & Meng Wang & Mohamed Nadhir Djekidel & Huan Chen & Di Liu & Frederick W. Alt & Yi Zhang, 2021. "eccDNAs are apoptotic products with high innate immunostimulatory activity," Nature, Nature, vol. 599(7884), pages 308-314, November.
    • Handle: RePEc:nat:nature:v:599:y:2021:i:7884:d:10.1038_s41586-021-04009-w
    DOI: 10.1038/s41586-021-04009-w
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    Cited by:

    1. Jinxin Phaedo Chen & Constantin Diekmann & Honggui Wu & Chong Chen & Giulia Chiara & Enrico Berrino & Konstantinos L. Georgiadis & Britta A. M. Bouwman & Mohit Virdi & Luuk Harbers & Sara Erika Bellom, 2024. "scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Xuyuan Gao & Ke Liu & Songwen Luo & Meifang Tang & Nianping Liu & Chen Jiang & Jingwen Fang & Shouzhen Li & Yanbing Hou & Chuang Guo & Kun Qu, 2024. "Comparative analysis of methodologies for detecting extrachromosomal circular DNA," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Panpan Zhang & Assane Mbodj & Abirami Soundiramourtty & Christel Llauro & Alain Ghesquière & Mathieu Ingouff & R. Keith Slotkin & Frédéric Pontvianne & Marco Catoni & Marie Mirouze, 2023. "Extrachromosomal circular DNA and structural variants highlight genome instability in Arabidopsis epigenetic mutants," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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