MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch
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MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch. / Jakobsen, Simon T.; Jensen, Rikke A.M.; Madsen, Maria S.; Ravnsborg, Tina; Vaagenso, Christian S.; Siersbæk, Majken S.; Einarsson, Hjorleifur; Andersson, Robin; Jensen, Ole N.; Siersbæk, Rasmus.
I: Nature Genetics, Bind 56, 2024, s. 663–674.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch
AU - Jakobsen, Simon T.
AU - Jensen, Rikke A.M.
AU - Madsen, Maria S.
AU - Ravnsborg, Tina
AU - Vaagenso, Christian S.
AU - Siersbæk, Majken S.
AU - Einarsson, Hjorleifur
AU - Andersson, Robin
AU - Jensen, Ole N.
AU - Siersbæk, Rasmus
N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024..
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-024-01676-z
DO - 10.1038/s41588-024-01676-z
M3 - Journal article
AN - SCOPUS:85186940287
VL - 56
SP - 663
EP - 674
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -
ID: 386375674