Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma.
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Date
2018-04-01Author
Zeid, R
Lawlor, MA
Poon, E
Reyes, JM
Fulciniti, M
Lopez, MA
Scott, TG
Nabet, B
Erb, MA
Winter, GE
Jacobson, Z
Polaski, DR
Karlin, KL
Hirsch, RA
Munshi, NP
Westbrook, TF
Chesler, L
Lin, CY
Bradner, JE
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Chromatin
Humans
Neuroblastoma
Nuclear Proteins
Gene Amplification
Binding Sites
Kinetics
Oncogenes
Genes, myc
Enhancer Elements, Genetic
Promoter Regions, Genetic
Twist-Related Protein 1
N-Myc Proto-Oncogene Protein
Research team
Paediatric Solid Tumour Biology and Therapeutics
Language
eng
Date accepted
2017-12-18
License start date
2018-04
Citation
Nature genetics, 2018, 50 (4), pp. 515 - 523
Publisher
NATURE PUBLISHING GROUP