Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
RG Development & Disease, Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195, Berlin, Germany.
Nat Commun. 2020 Nov 16;11(1):5823. doi: 10.1038/s41467-020-19452-y.
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 扩增驱动了六分之一的神经母细胞瘤病例。这些额外的基因拷贝通常存在于高度重排的、染色体外的环状 DNA（ecDNA）上。迄今为止，尚未描述确切的扩增子结构，其重排的功能相关性尚不清楚。在这里，我们使用短读长和纳米孔测序分析 MYCN 扩增子结构，并使用 ChIP-seq、ATAC-seq 和 Hi-C 分析其染色质景观。这揭示了两种不同类别的扩增子，它们解释了 MYCN 过表达的调节要求。第一类总是共同扩增由去甲肾上腺素能核心调节回路（CRC）驱动的近端增强子。第二类 MYCN 扩增子的特点是结构高度复杂，缺乏关键的局部增强子，而是包含携带 CRC 驱动增强子的远端染色体片段。因此，异位增强子劫持可以弥补局部基因调控元件的缺失，并解释了在 MYCN 扩增中观察到的结构多样性的很大一部分。
