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dc.contributor.authorZeid, R
dc.contributor.authorLawlor, MA
dc.contributor.authorPoon, E
dc.contributor.authorReyes, JM
dc.contributor.authorFulciniti, M
dc.contributor.authorLopez, MA
dc.contributor.authorScott, TG
dc.contributor.authorNabet, B
dc.contributor.authorErb, MA
dc.contributor.authorWinter, GE
dc.contributor.authorJacobson, Z
dc.contributor.authorPolaski, DR
dc.contributor.authorKarlin, KL
dc.contributor.authorHirsch, RA
dc.contributor.authorMunshi, NP
dc.contributor.authorWestbrook, TF
dc.contributor.authorChesler, L
dc.contributor.authorLin, CY
dc.contributor.authorBradner, JE
dc.date.accessioned2019-04-03T08:23:19Z
dc.date.issued2018-04
dc.identifier.citationNature genetics, 2018, 50 (4), pp. 515 - 523
dc.identifier.issn1061-4036
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3168
dc.identifier.eissn1546-1718
dc.identifier.doi10.1038/s41588-018-0044-9
dc.description.abstractAmplification 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.
dc.formatPrint-Electronic
dc.format.extent515 - 523
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectChromatin
dc.subjectHumans
dc.subjectNeuroblastoma
dc.subjectNuclear Proteins
dc.subjectGene Amplification
dc.subjectBinding Sites
dc.subjectKinetics
dc.subjectOncogenes
dc.subjectGenes, myc
dc.subjectEnhancer Elements, Genetic
dc.subjectPromoter Regions, Genetic
dc.subjectTwist-Related Protein 1
dc.subjectN-Myc Proto-Oncogene Protein
dc.titleEnhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma.
dc.typeJournal Article
dcterms.dateAccepted2017-12-18
rioxxterms.versionofrecord10.1038/s41588-018-0044-9
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature genetics
pubs.issue4
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.publication-statusPublished
pubs.volume50
pubs.embargo.termsNot known
icr.researchteamPaediatric Solid Tumour Biology and Therapeuticsen_US
dc.contributor.icrauthorChesler, Louisen
dc.contributor.icrauthorPoon, Evonen


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