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bioRxiv · 10.1101/2024.09.17.613488

Extrachromosomal DNA Associates with Nuclear Condensates and Reorganizes Chromatin Structures to Enhance Oncogenic Transcription

Taghbalout, A.·Tung, C.-H.·Clow, P. A.·Wang, P.·Tjong, H.·Wong, C. H.·Mao, D. D.·Maurya, R.·Huang, M.-F.·Ngan, C. Y.·Kim, A. H.·Wei, C.-L.
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Abstract

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting liquid-liquid phase separation breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans-activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for novel therapeutic strategies in cancer treatment.

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Taghbalout, A., Tung, C.-H., Clow, P. A., Wang, P., Tjong, H., Wong, C. H., Mao, D. D., Maurya, R., Huang, M.-F., Ngan, C. Y., Kim, A. H., Wei, C.-L.. 2024-09-20. Extrachromosomal DNA Associates with Nuclear Condensates and Reorganizes Chromatin Structures to Enhance Oncogenic Transcription. https://doi.org/10.1101/2024.09.17.613488

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