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  ecDNA hubs drive cooperative intermolecular oncogene expression

Hung, K. L., Yost, K. E., Xie, L., Shi, Q., Helmsauer, K., Luebeck, J., et al. (2021). ecDNA hubs drive cooperative intermolecular oncogene expression. Nature, 600, 731-736. doi:10.1038/s41586-021-04116-8.

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Hung, King L. , Author
Yost, Kathryn E. , Author
Xie, Liangqi, Author
Shi, Quanming , Author
Helmsauer, Konstantin , Author
Luebeck, Jens, Author
Schöpflin, Robert, Author
Lange, Joshua T. , Author
Chamorro González, Rocío , Author
Weiser, Natasha E. , Author
Chen, Celine , Author
Valieva, Maria1, Author              
Wong, Ivy Tsz-Lo , Author
Wu, Sihan, Author
Dehkordi, Siavash R. , Author
Duffy, Connor V. , Author
Kraft, Katerina , Author
Tang, Jun, Author
Belk, Julia A. , Author
Rose, John C., Author
Corces, M. Ryan , AuthorGranja, Jeffrey M. , AuthorLi, Rui, AuthorRajkumar, Utkrisht , AuthorFriedlein, Jordan , AuthorBagchi, Anindya , AuthorSatpathy, Ansuman T. , AuthorTjian, Robert , AuthorMundlos, Stefan1, Author              Bafna, Vineet , AuthorHenssen, Anton G. , AuthorMischel, Paul S. , AuthorLiu, Zhe, AuthorChang, Howard Y. , Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 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-boundPVT1 promoter is ectopically fused to MYCand duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1promoter 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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Language(s): eng - English
 Dates: 2021-10-082021-11-24
 Publication Status: Published online
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1038/s41586-021-04116-8
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: 6 Volume / Issue: 600 Sequence Number: - Start / End Page: 731 - 736 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238