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

Nat Genet. 2024 Apr;56(4):663-674. doi: 10.1038/s41588-024-01676-z. Epub 2024 Mar 7.

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.

MeSH terms

  • 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
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Transcription Factors* / genetics

Substances

  • Transcription Factors
  • Nuclear Proteins
  • RNA Polymerase II
  • Proto-Oncogene Proteins c-myc
  • BRD4 protein, human
  • Bromodomain Containing Proteins
  • Cell Cycle Proteins