scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells

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 Bellomo, Caterina Marchiò, Magda Bienko () and Nicola Crosetto ()
Additional contact information
Jinxin Phaedo Chen: Tumor and Cell Biology, Karolinska Institutet
Constantin Diekmann: Tumor and Cell Biology, Karolinska Institutet
Honggui Wu: Peking University
Chong Chen: West China Hospital, Sichuan University
Giulia Chiara: Viale Rita Levi-Montalcini 1
Enrico Berrino: FPO – IRCCS, Candiolo, SP142, km 3,95
Konstantinos L. Georgiadis: Science for Life Laboratory, Tomtebodavägen 23A
Britta A. M. Bouwman: Tumor and Cell Biology, Karolinska Institutet
Mohit Virdi: Viale Rita Levi-Montalcini 1
Luuk Harbers: Tumor and Cell Biology, Karolinska Institutet
Sara Erika Bellomo: FPO – IRCCS, Candiolo, SP142, km 3,95
Caterina Marchiò: FPO – IRCCS, Candiolo, SP142, km 3,95
Magda Bienko: Tumor and Cell Biology, Karolinska Institutet
Nicola Crosetto: Tumor and Cell Biology, Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Extrachromosomal circular DNAs (eccDNAs) have emerged as important intra-cellular mobile genetic elements that affect gene copy number and exert in trans regulatory roles within the cell nucleus. Here, we describe scCircle-seq, a method for profiling eccDNAs and unraveling their diversity and complexity in single cells. We implement and validate scCircle-seq in normal and cancer cell lines, demonstrating that most eccDNAs vary largely between cells and are stochastically inherited during cell division, although their genomic landscape is cell type-specific and can be used to accurately cluster cells of the same origin. eccDNAs are preferentially produced from chromatin regions enriched in H3K9me3 and H3K27me3 histone marks and are induced during replication stress conditions. Concomitant sequencing of eccDNAs and RNA from the same cell uncovers the absence of correlation between eccDNA copy number and gene expression levels, except for a few oncogenes, including MYC, contained within a large eccDNA in colorectal cancer cells. Lastly, we apply scCircle-seq to one prostate cancer and two breast cancer specimens, revealing cancer-specific eccDNA landscapes and a higher propensity of eccDNAs to form in amplified genomic regions. scCircle-seq is a scalable tool that can be used to dissect the complexity of eccDNAs across different cell and tissue types, and further expands the potential of eccDNAs for cancer diagnostics.

Date: 2024
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DOI: 10.1038/s41467-024-45972-y

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