Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.
Acetylation
Base Sequence
Cell Line, Tumor
Chromosomes, Human
/ genetics
DNA Methylation
/ genetics
DNA, Circular
/ genetics
Enhancer Elements, Genetic
/ genetics
Epigenesis, Genetic
Histones
/ metabolism
Humans
Kaplan-Meier Estimate
Lysine
/ metabolism
N-Myc Proto-Oncogene Protein
/ genetics
Nanopore Sequencing
Neuroblastoma
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 11 2020
16 11 2020
Historique:
received:
20
12
2019
accepted:
30
09
2020
entrez:
17
11
2020
pubmed:
18
11
2020
medline:
26
11
2020
Statut:
epublish
Résumé
MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA (ecDNA). The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyze the MYCN amplicon structure using short-read and Nanopore sequencing and its chromatin landscape using ChIP-seq, ATAC-seq and Hi-C. This reveals two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplifies a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons is characterized by high structural complexity, lacks key local enhancers, and instead contains distal chromosomal fragments harboring CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.
Identifiants
pubmed: 33199677
doi: 10.1038/s41467-020-19452-y
pii: 10.1038/s41467-020-19452-y
pmc: PMC7669906
doi:
Substances chimiques
DNA, Circular
0
Histones
0
N-Myc Proto-Oncogene Protein
0
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5823Subventions
Organisme : Wellcome Trust
ID : 206475/Z/17/Z
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
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