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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 et al_2021.pdf (Verlagsversion), 20MB
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© 2021, The Author(s), under exclusive licence to Springer Nature Limited
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 Urheber:
Hung, King L. , Autor
Yost, Kathryn E. , Autor
Xie, Liangqi, Autor
Shi, Quanming , Autor
Helmsauer, Konstantin , Autor
Luebeck, Jens, Autor
Schöpflin, Robert, Autor
Lange, Joshua T. , Autor
Chamorro González, Rocío , Autor
Weiser, Natasha E. , Autor
Chen, Celine , Autor
Valieva, Maria1, Autor           
Wong, Ivy Tsz-Lo , Autor
Wu, Sihan, Autor
Dehkordi, Siavash R. , Autor
Duffy, Connor V. , Autor
Kraft, Katerina , Autor
Tang, Jun, Autor
Belk, Julia A. , Autor
Rose, John C., Autor
Corces, M. Ryan , AutorGranja, Jeffrey M. , AutorLi, Rui, AutorRajkumar, Utkrisht , AutorFriedlein, Jordan , AutorBagchi, Anindya , AutorSatpathy, Ansuman T. , AutorTjian, Robert , AutorMundlos, Stefan1, Autor           Bafna, Vineet , AutorHenssen, Anton G. , AutorMischel, Paul S. , AutorLiu, Zhe, AutorChang, Howard Y. , Autor mehr..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2021-10-082021-11-24
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1038/s41586-021-04116-8
 Art des Abschluß: -

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Titel: Nature
  Kurztitel : Nature
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: London : Nature Publishing Group
Seiten: 6 Band / Heft: 600 Artikelnummer: - Start- / Endseite: 731 - 736 Identifikator: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238