Circular ecDNA promotes accessible chromatin and high oncogene expression

Menée sur des lignées cellulaires de cancer de la prostate, de cancer du côlon et de glioblastome et menée à l'aide de techniques récentes de microscopie, cette étude met en évidence la structure de l'ADN extrachromosomique circulaire, le faible niveau de compactage de sa chromatine ainsi que la forte expression intratumorale de ses oncogènes

Résumé en anglais

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.