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ecDNA hubs drive cooperative intermolecular oncogene expression.
Hung, King L; Yost, Kathryn E; Xie, Liangqi; Shi, Quanming; Helmsauer, Konstantin; Luebeck, Jens; Schöpflin, Robert; Lange, Joshua T; Chamorro González, Rocío; Weiser, Natasha E; Chen, Celine; Valieva, Maria E; Wong, Ivy Tsz-Lo; Wu, Sihan; Dehkordi, Siavash R; Duffy, Connor V; Kraft, Katerina; Tang, Jun; Belk, Julia A; Rose, John C; Corces, M Ryan; Granja, Jeffrey M; Li, Rui; Rajkumar, Utkrisht; Friedlein, Jordan; Bagchi, Anindya; Satpathy, Ansuman T; Tjian, Robert; Mundlos, Stefan; Bafna, Vineet; Henssen, Anton G; Mischel, Paul S; Liu, Zhe; Chang, Howard Y.
Afiliación
  • 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.
  • Shi Q; 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.
  • Helmsauer K; Howard Hughes Medical Institute, Berkeley, CA, USA.
  • Luebeck J; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Schöpflin R; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Lange JT; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA.
  • Chamorro González R; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
  • Weiser NE; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Chen C; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Valieva ME; Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Wong IT; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Wu S; ChEM-H, Stanford University, Stanford, CA, USA.
  • Dehkordi SR; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Duffy CV; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Kraft K; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Tang J; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Belk JA; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Rose JC; Development and Disease Research Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • Corces MR; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Granja JM; ChEM-H, Stanford University, Stanford, CA, USA.
  • Li R; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Rajkumar U; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Friedlein J; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
  • Bagchi A; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Satpathy AT; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Tjian R; ChEM-H, Stanford University, Stanford, CA, USA.
  • Mundlos S; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Bafna V; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Henssen AG; Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Mischel PS; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Liu Z; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
  • Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
Nature ; 600(7890): 731-736, 2021 12.
Article en En | MEDLINE | ID: mdl-34819668
ABSTRACT
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Nucleares / Neoplasias Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas Nucleares / Neoplasias Límite: Humans Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos