MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch.

Autor: Jakobsen ST; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Jensen RAM; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Madsen MS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Ravnsborg T; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Vaagenso CS; Department of Biology, University of Copenhagen, Copenhagen, Denmark., Siersbæk MS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Einarsson H; Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Andersson R; Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jensen ON; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Siersbæk R; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. siersbaek@bmb.sdu.dk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Apr; Vol. 56 (4), pp. 663-674. Date of Electronic Publication: 2024 Mar 07.
DOI: 10.1038/s41588-024-01676-z
Abstrakt: The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC directly regulates enhancer activity to promote cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNA polymerase II (RNAPII), rather than regulating RNAPII pause-release, as is the case at promoters. This process is mediated by MYC-induced H3K9 demethylation and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. We propose that MYC drives prognostic cancer type-specific gene programs through induction of an enhancer-specific epigenetic switch, which can be targeted by BET and GCN5 inhibitors.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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