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

Simon T. Jakobsen, Rikke A.M. Jensen, Maria S. Madsen, Tina Ravnsborg, Christian S. Vaagenso, Majken S. Siersbæk, Hjorleifur Einarsson, Robin Andersson, Ole N. Jensen, Rasmus Siersbæk*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalNature Genetics
Volume56
Issue number4
Pages (from-to)663–674
ISSN1061-4036
DOIs
Publication statusPublished - Apr 2024

Keywords

  • Bromodomain Containing Proteins
  • Cell Cycle Proteins/genetics
  • Enhancer Elements, Genetic/genetics
  • Epigenesis, Genetic
  • Humans
  • Neoplasms/genetics
  • Nuclear Proteins/genetics
  • Prognosis
  • Proto-Oncogene Proteins c-myc/genetics
  • RNA Polymerase II/genetics
  • Transcription Factors/genetics

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