Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma

Konstantin Helmsauer, Maria E. Valieva, Salaheddine Ali, Rocío Chamorro González, Robert Schöpflin, Claudia Röefzaad, Yi Bei, Heathcliff Dorado Garcia, Elias Rodriguez-Fos, Montserrat Puiggròs, Katharina Kasack, Kerstin Haase, Csilla Keskeny, Celine Y. Chen, Luis P. Kuschel, Philipp Euskirchen, Verena Heinrich, Michael I. Robson, Carolina Rosswog, Joern Toedling, Annabell Szymansky, Falk Hertwig, Matthias Fischer, David Torrents, Angelika Eggert, Johannes H. Schulte, Stefan Mundlos, Anton G. Henssen () and Richard P. Koche ()
Additional contact information
Konstantin Helmsauer: Charité—Universitätsmedizin Berlin
Maria E. Valieva: Max Planck Institute for Molecular Genetics
Salaheddine Ali: Max Planck Institute for Molecular Genetics
Rocío Chamorro González: Charité—Universitätsmedizin Berlin
Robert Schöpflin: Max Planck Institute for Molecular Genetics
Claudia Röefzaad: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Yi Bei: Charité—Universitätsmedizin Berlin
Heathcliff Dorado Garcia: Charité—Universitätsmedizin Berlin
Elias Rodriguez-Fos: Joint BSC-CRG-IRB Research Program in Computational Biology
Montserrat Puiggròs: Joint BSC-CRG-IRB Research Program in Computational Biology
Katharina Kasack: partner site Berlin, and German Cancer Research Center DKFZ
Kerstin Haase: Charité—Universitätsmedizin Berlin
Csilla Keskeny: Charité—Universitätsmedizin Berlin
Celine Y. Chen: Charité—Universitätsmedizin Berlin
Luis P. Kuschel: Charité—Universitätsmedizin Berlin
Philipp Euskirchen: partner site Berlin, and German Cancer Research Center DKFZ
Verena Heinrich: Max Planck Institute for Molecular Genetics
Michael I. Robson: Max Planck Institute for Molecular Genetics
Carolina Rosswog: University of Cologne
Joern Toedling: Charité—Universitätsmedizin Berlin
Annabell Szymansky: Charité—Universitätsmedizin Berlin
Falk Hertwig: Charité—Universitätsmedizin Berlin
Matthias Fischer: University of Cologne
David Torrents: Joint BSC-CRG-IRB Research Program in Computational Biology
Angelika Eggert: Charité—Universitätsmedizin Berlin
Johannes H. Schulte: Charité—Universitätsmedizin Berlin
Stefan Mundlos: Max Planck Institute for Molecular Genetics
Anton G. Henssen: Charité—Universitätsmedizin Berlin
Richard P. Koche: Berlin Institute of Health

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19452-y

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