Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma

Nat Genet. 2018 Apr;50(4):515-523. doi: 10.1038/s41588-018-0044-9. Epub 2018 Jan 29.


Amplification of the locus encoding the oncogenic transcription factor MYCN is a defining feature of high-risk neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of MYCN perturbation in neuroblastoma. At oncogenic levels, MYCN associates with E-box binding motifs in an affinity-dependent manner, binding to strong canonical E-boxes at promoters and invading abundant weaker non-canonical E-boxes clustered at enhancers. Loss of MYCN leads to a global reduction in transcription, which is most pronounced at MYCN target genes with the greatest enhancer occupancy. These highly occupied MYCN target genes show tissue-specific expression and are linked to poor patient survival. The activity of genes with MYCN-occupied enhancers is dependent on the tissue-specific transcription factor TWIST1, which co-occupies enhancers with MYCN and is required for MYCN-dependent proliferation. These data implicate tissue-specific enhancers in defining often highly tumor-specific 'MYC target gene signatures' and identify disruption of the MYCN enhancer regulatory axis as a promising therapeutic strategy in neuroblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / genetics
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism
  • Enhancer Elements, Genetic
  • Gene Amplification
  • Genes, myc
  • Humans
  • Kinetics
  • N-Myc Proto-Oncogene Protein / genetics*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • Nuclear Proteins / metabolism
  • Oncogenes
  • Promoter Regions, Genetic
  • Twist-Related Protein 1 / metabolism


  • Chromatin
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • TWIST1 protein, human
  • Twist-Related Protein 1