Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.
Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma.
复制标题
增强子劫持决定神经母细胞瘤中染色体外环状MYCN扩增子结构。
DOI：
10.1038/s41467-020-19452-y
复制
发表时间：
2020-11-16
影响因子：
16.6
通讯作者：
Koche RP
中科院分区：
文献类型：
--
作者：
Helmsauer K;Valieva ME;Ali S;Chamorro González R;Schöpflin R;Röefzaad C;Bei Y;Dorado Garcia H;Rodriguez-Fos E;Puiggròs M;Kasack K;Haase K;Keskeny C;Chen CY;Kuschel LP;Euskirchen P;Heinrich V;Robson MI;Rosswog C;Toedling J;Szymansky A;Hertwig F;Fischer M;Torrents D;Eggert A;Schulte JH;Mundlos S;Henssen AG;Koche RP
MYCN扩增驱动六分之一的神经母细胞瘤病例。多余的基因拷贝通常存在于高度重排的染色体外环状DNA（ecDNA）上。确切的扩增子结构迄今尚未描述，其重排的功能相关性是未知的。在这里，我们使用短读和纳米孔测序分析MYCN扩增子结构，并使用ChIP-seq，ATAC-seq和Hi-C分析其染色质景观。这揭示了两类不同的扩增子，解释了MYCN过表达的调控要求。第一类总是共放大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扩增子的特征在于高结构复杂性，缺乏关键的局部增强子，而是含有含有CRC驱动的增强子的远端染色体片段。因此，异位增强子劫持可以补偿局部基因调控元件的丢失，并解释了MYCN扩增中观察到的结构多样性的大部分。MYCN扩增在神经母细胞瘤中很常见。在这里，作者通过整合短和长的基因组和表观基因组数据分析了MYCN扩增子结构及其表观遗传调控，并在神经母细胞瘤中发现了两类MYCN扩增子，一类由局部增强子驱动，另一类由远端调控元件劫持驱动。
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.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E
影响因子：
9.3
作者：
Durand NC;Shamim MS;Machol I;Rao SS;Huntley MH;Lander ES;Aiden EL
通讯作者：
Aiden EL
影响因子：
16.6
作者：
Decaesteker B;Denecker G;Van Neste C;Dolman EM;Van Loocke W;Gartlgruber M;Nunes C;De Vloed F;Depuydt P;Verboom K;Rombaut D;Loontiens S;De Wyn J;Kholosy WM;Koopmans B;Essing AHW;Herrmann C;Dreidax D;Durinck K;Deforce D;Van Nieuwerburgh F;Henssen A;Versteeg R;Boeva V;Schleiermacher G;van Nes J;Mestdagh P;Vanhauwaert S;Schulte JH;Westermann F;Molenaar JJ;De Preter K;Speleman F
通讯作者：
Speleman F
影响因子：
64.5
作者：
Hadi K;Yao X;Behr JM;Deshpande A;Xanthopoulakis C;Tian H;Kudman S;Rosiene J;Darmofal M;DeRose J;Mortensen R;Adney EM;Shaiber A;Gajic Z;Sigouros M;Eng K;Wala JA;Wrzeszczyński KO;Arora K;Shah M;Emde AK;Felice V;Frank MO;Darnell RB;Ghandi M;Huang F;Dewhurst S;Maciejowski J;de Lange T;Setton J;Riaz N;Reis-Filho JS;Powell S;Knowles DA;Reznik E;Mishra B;Beroukhim R;Zody MC;Robine N;Oman KM;Sanchez CA;Kuhner MK;Smith LP;Galipeau PC;Paulson TG;Reid BJ;Li X;Wilkes D;Sboner A;Mosquera JM;Elemento O;Imielinski M
通讯作者：
Imielinski M
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK