Zoe Jacobson, Michael A. Erb, Evon Poon, Georg E. Winter, Michael A. Lopez, Matthew A. Lawlor, Donald R. Polaski, Behnam Nabet, Charles Y. Lin, Rhamy Zeid, Louis Chesler, Mariateresa Fulciniti, James E. Bradner, Rachel A. Hirsch, Nikhil P. Munshi, Thomas G. Scott, Thomas F. Westbrook, Jaime M. Reyes, Kristen L. Karlin
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.