Engineered extrachromosomal circular DNAs promote tumorigenesis (WGS)
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ABSTRACT:
PROVIDER: PRJNA1100545 | ENA |
REPOSITORIES: ENA
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Project description:Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general strategy to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in genetically engineered mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harboring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization, and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumor formation in an autochthonous mouse model of hepatocellular carcinoma.
2024-10-05 | GSE264005 | GEO
Project description:Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general strategy to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in genetically engineered mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harboring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization, and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumor formation in an autochthonous mouse model of hepatocellular carcinoma.
2024-10-05 | GSE264003 | GEO
Project description:Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general strategy to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in genetically engineered mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harboring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization, and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumor formation in an autochthonous mouse model of hepatocellular carcinoma.
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Project description:Engineered extrachromosomal oncogene amplifications promote tumorigenesis
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Project description:Oncogenic extrachromosomal DNAs (ecDNA) are common in cancers, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe scEC&T-seq, a method for parallel isolation and sequencing of extrachromosomal circular DNAs and full-length mRNA from single human cells. By applying scEC&T-seq to cancer cells, we not only describe intercellular differences in ecDNA content, but also investigate their structural heterogeneity and transcriptional impact. We reveal that whereas oncogene-containing ecDNA elements are clonally present in cancer cells and drive intercellular oncogene expression differences, other small circular DNAs also captured by scEC&T-seq are mostly private to individual cancer cells, indicating differences in selection and propagation. Moreover, scEC&T-seq uncovers intercellular differences in ecDNA structure, which allowed the inference of ecDNA structural dynamics and point to circular recombination as a potential mechanism of ecDNA evolution. We envision that our method may enable the analysis of yet unknown prerequisites for the maintenance of both small and large circular DNA in cancers, but also in the context of other diseases and normal cellular development.
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Project description:Engineered extrachromosomal oncogene amplifications promote tumorigenesis (RNA-Seq)
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Project description:Extrachromosomal circular DNA (eccDNA) is double-stranded circular DNA that is derived from but independent of chromosomal DNA. Owing to its nonchromosomal inheritance, eccDNA facilitates the amplification of oncogenes and expedites the process of genome evolution in tumor. However, the role of eccDNA in RB remains enigmatic. We combined Circle-Seq and RNA-Seq to identified crucial extrachromosomal circular oncogene amplicons. Herein, we revealed that extrachromosomal circular SUZ12 amplicon regulates H3K27me3 modification during the oncogenic progression of retinoblastoma. Conclusively, our study initially delineated an integrated picture of the eccDNA landscape in retinoblastoma and unveiled a novel SUZ12-containing eccDNA/H3K27me3 oncogenic mechanism where eccDNA dictates retinoblastoma progression through regulating transcription levels of linear DNA.
2023-07-02 | GSE235888 | GEO
Project description:Effects of nucleases on cell-free extrachromosomal circular DNA
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Project description:We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200-400 bp long, derived from unique non-repetitive sequence and are enriched in the 5' untranslated regions of genes, exons and CpG islands. Chromosomal loci that are enriched sources of microDNA in adult brain are somatically mosaic for micro-deletions that appear to arise from the excision of microDNAs. Germline microdeletions identified by the "Thousand Genomes" project may also arise from the excision of microDNAs in the germline lineage. We have thus identified a new DNA entity in mammalian cells and provide evidence that their generation leaves behind deletions in different genomic loci. Circular DNA profiling by high throughput sequencing
2012-02-27 | E-GEOD-36088 | biostudies-arrayexpress
Project description:Extrachromosomal circular DNAs are ubiquitous in mouse hearts and function as enhancers to promote chromosomal transcription [Circle-seq]
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