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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

  • Simon T. Jakobsen
  • Rikke A.M. Jensen
  • Maria S. Madsen
  • Tina Ravnsborg
  • Christian S. Vaagenso
  • Majken S. Siersbæk
  • Hjorleifur Einarsson
  • Andersson, Robin
  • Ole N. Jensen
  • Rasmus Siersbæk
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.
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind56
Sider (fra-til)663–674
Antal sider12
ISSN1061-4036
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
Sequencing was carried out at the Center for Functional Genomics and Tissue Plasticity, in the Functional Genomics and Metabolism research unit at SDU. The authors thank T. P. Mortensen, M. Wishoff, G. Jørgensen, and R. Nielsen for sequencing assistance. Work in the R.S. laboratory was supported by the Novo Nordisk Foundation (NNF18OC0053276 and NNF21OC0071373 to R.S.), the Danish Cancer Society (R231-A13786 to R.S.), and the VILLUM Foundation (project no. 42066 to R.S.). The mass spectrometry and proteomics platform at SDU, used to perform qPLEX-RIME, was financed by grants from the VILLUM Foundation (VILLUM Center for Bioanalytical Sciences, grant no. 7292 to O.N.J.), the Novo Nordisk Foundation (INTEGRA grant no. NNF20OC0061575 to O.N.J.), and by PRO-MS: Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B to O.N.J.). The work in the R.A. laboratory was supported by the Novo Nordisk Foundation (NNF20OC0059796 and NNF21SA0072102 to R.A.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024..

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