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Enhancer hijacking determines intra- and extrachromosomal circular MYCN amplicon architecture in neuroblastoma

Publication

Date: 20th December 2019 | Source: BioRxiv

Authors: Konstantin Helmsauer, Maria Valieva, Salaheddine Ali, Rocio Chamorro Gonzalez, Robert Schöpflin, Claudia Röefzaad, Yi Bei, Heathcliff Dorado Garcia, Elias Rodriguez-Fos, Montserrat Puiggròs, Katharina Kasack, Kerstin Haase, Luis P. Kuschel, Philipp Euskirchen, Verena Heinrich, Michael Robson, Carolina Rosswog, Jörn Tödling, Annabell Szymansky, Falk Hertwig, Matthias Fischer, David Torrents, Angelika Eggert, Johannes H. Schulte, Stefan Mundlos, Anton G. Henssen, Richard P. Koche.

MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown.

Here, we analyzed the MYCN amplicon structure and its chromatin landscape.

This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored 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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