Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2018-04-01
Date Accepted
2017-12-18
Abstract
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.
Citation
Nature genetics, 2018, 50 (4), pp. 515 - 523
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1061-4036
eISSN
1546-1718
Research Team
Paediatric Solid Tumour Biology and Therapeutics