dc.contributor.author | Zeid, R | |
dc.contributor.author | Lawlor, MA | |
dc.contributor.author | Poon, E | |
dc.contributor.author | Reyes, JM | |
dc.contributor.author | Fulciniti, M | |
dc.contributor.author | Lopez, MA | |
dc.contributor.author | Scott, TG | |
dc.contributor.author | Nabet, B | |
dc.contributor.author | Erb, MA | |
dc.contributor.author | Winter, GE | |
dc.contributor.author | Jacobson, Z | |
dc.contributor.author | Polaski, DR | |
dc.contributor.author | Karlin, KL | |
dc.contributor.author | Hirsch, RA | |
dc.contributor.author | Munshi, NP | |
dc.contributor.author | Westbrook, TF | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Lin, CY | |
dc.contributor.author | Bradner, JE | |
dc.date.accessioned | 2019-04-03T08:23:19Z | |
dc.date.issued | 2018-04-01 | |
dc.identifier.citation | Nature genetics, 2018, 50 (4), pp. 515 - 523 | |
dc.identifier.issn | 1061-4036 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3168 | |
dc.identifier.eissn | 1546-1718 | |
dc.identifier.doi | 10.1038/s41588-018-0044-9 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 515 - 523 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Chromatin | |
dc.subject | Humans | |
dc.subject | Neuroblastoma | |
dc.subject | Nuclear Proteins | |
dc.subject | Gene Amplification | |
dc.subject | Binding Sites | |
dc.subject | Kinetics | |
dc.subject | Oncogenes | |
dc.subject | Genes, myc | |
dc.subject | Enhancer Elements, Genetic | |
dc.subject | Promoter Regions, Genetic | |
dc.subject | Twist-Related Protein 1 | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-12-18 | |
rioxxterms.versionofrecord | 10.1038/s41588-018-0044-9 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature genetics | |
pubs.issue | 4 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 50 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Chesler, Louis | |