Helmsauer, Konstantin ORCID: 0000-0003-0773-4114, Valieva, Maria E., Ali, Salaheddine, Gonzalez, Rocio Chamorro, Schoepflin, Robert, Roeefzaad, Claudia, Bei, Yi, Garcia, Heathcliff Dorado, Rodriguez-Fos, Elias ORCID: 0000-0002-2555-0178, Puiggros, Montserrat, Kasack, Katharina, Haase, Kerstin, Keskeny, Csilla, Chen, Celine Y., Kuschel, Luis P., Euskirchen, Philipp, Heinrich, Verena, Robson, Michael, I, Rosswog, Carolina, Toedling, Joern, Szymansky, Annabell, Hertwig, Falk, Fischer, Matthias, Torrents, David, Eggert, Angelika, Schulte, Johannes H., Mundlos, Stefan, Henssen, Anton G. and Koche, Richard P. (2020). Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nat. Commun., 11 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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. MYCN amplification is common in neuroblastomas. Here the authors analyse the MYCN amplicon structure and its epigenetic regulation by integrating short- and longread genomic and epigenomic data and find two classes of MYCN amplicons in neuroblastomas, one driven by local enhancers and the other by hijacking of distal regulatory elements.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Helmsauer, KonstantinUNSPECIFIEDorcid.org/0000-0003-0773-4114UNSPECIFIED
Valieva, Maria E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, SalaheddineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, Rocio ChamorroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoepflin, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roeefzaad, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bei, YiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia, Heathcliff DoradoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez-Fos, EliasUNSPECIFIEDorcid.org/0000-0002-2555-0178UNSPECIFIED
Puiggros, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kasack, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haase, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keskeny, CsillaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Celine Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuschel, Luis P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Euskirchen, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinrich, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robson, Michael, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosswog, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toedling, JoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szymansky, AnnabellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hertwig, FalkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torrents, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henssen, Anton G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koche, Richard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-311306
DOI: 10.1038/s41467-020-19452-y
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOMOGENEOUSLY STAINING REGIONS; STRUCTURAL VARIATION; DOUBLE MINUTES; COPY NUMBER; GENOME; DNA; CHROMATIN; REARRANGEMENTS; AMPLIFICATION; ACTIVATIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31130

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