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Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma

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Item Type:Article
Title:Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma
Creators Name:Helmsauer, K. and Valieva, M.E. and Ali, S. and Chamorro Gonzalez, R. and Schöpflin, R. and Röefzaad, C. and Bei, Y. and Dorado Garcia, H. and Rodriguez-Fos, E. and Puiggròs, M. and Kasack, K. and Haase, K. and Keskeny, C. and Chen, C.Y. and Kuschel, L.P. and Euskirchen, P. and Heinrich, V. and Robson, M.I. and Rosswog, C. and Toedling, J. and Szymansky, A. and Hertwig, F. and Fischer, M. and Torrents, D. and Eggert, A. and Schulte, J.H. and Mundlos, S. and Henssen, A.G. and Koche, R.P.
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.
Keywords:Acetylation, Base Sequence, Circular DNA, DNA Methylation, Genetic Enhancer Elements, Genetic Epigenesis, Histones, Human Chromosomes, Kaplan-Meier Estimate, Lysine, N-Myc Proto-Oncogene Protein, Nanopore Sequencing, Neuroblastoma, Tumor Cell Line
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5823
Date:16 November 2020
Official Publication:https://doi.org/10.1038/s41467-020-19452-y
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/18644/Preprint version

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