Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma

Nature Communications
Konstantin HelmsauerRichard P. Koche

Abstract

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.

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Citations

Jan 22, 2021·Current Opinion in Genetics & Development·Sihan WuPaul S Mischel
Feb 23, 2021·Frontiers in Oncology·Ruochen LiuHongjuan Cui
May 1, 2021·International Journal of Molecular Sciences·Andrea MartisovaMartin Bartosik
Mar 18, 2021·Cancer Science·Atsushi Okabe, Atsushi Kaneda
Jun 12, 2021·Journal of Translational Medicine·Tianyi WangJiahai Shi
Aug 28, 2021·Journal of Personalized Medicine·Annabell SzymanskyJohannes H Schulte
Aug 24, 2021·Trends in Molecular Medicine·Annique Claringbould, Judith B Zaugg

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Methods Mentioned

BETA
Acetylation
immunoprecipitation
ChIP-seq
RNA-seq
Hi-C
genotyping
FCS
ChIP
PCR
Hi-Seq

Software Mentioned

Ensembl
TFBSTools
Subread package
Control
gGnome
Hi
deepTools
Picard
Juicer pipeline
MEM

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