ecDNA hubs drive cooperative intermolecular oncogene expression.

Autor: Hung KL; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Yost KE; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Xie L; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.; Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA, USA.; Howard Hughes Medical Institute, Berkeley, CA, USA., Shi Q; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Helmsauer K; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Luebeck J; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA., Schöpflin R; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany., Lange JT; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.; ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Chamorro González R; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Weiser NE; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Chen C; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Valieva ME; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany., Wong IT; ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Wu S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA., Dehkordi SR; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA., Duffy CV; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Kraft K; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Tang J; ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Belk JA; Department of Pathology, Stanford University, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA., Rose JC; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Corces MR; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Granja JM; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Li R; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA., Rajkumar U; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA., Friedlein J; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Bagchi A; Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Satpathy AT; Department of Pathology, Stanford University, Stanford, CA, USA., Tjian R; Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley, Berkeley, CA, USA.; Howard Hughes Medical Institute, Berkeley, CA, USA., Mundlos S; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany., Bafna V; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA., Henssen AG; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.; German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center DKFZ, Heidelberg, Germany.; Berlin Institute of Health, Berlin, Germany., Mischel PS; ChEM-H, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University, Stanford, CA, USA., Liu Z; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Dec; Vol. 600 (7890), pp. 731-736. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1038/s41586-021-04116-8
Abstrakt: Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation 1 . Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome 2,3 . Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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