3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.
3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.
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DOI：
10.1038/s41467-023-38044-0
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发表时间：
2023-04-21
影响因子：
16.6
通讯作者：
Chavez, Lukas
中科院分区：
文献类型：
--
作者：
Okonechnikov, Konstantin;Camgoez, Aylin;Chapman, Owen;Wani, Sameena;Park, Donglim Esther;Huebner, Jens-Martin;Chakraborty, Abhijit;Pagadala, Meghana;Bump, Rosalind;Chandran, Sahaana;Kraft, Katerina;Acuna-Hidalgo, Rocio;Reid, Derek;Sikkink, Kristin;Mauermann, Monika;Juarez, Edwin F.;Jenseit, Anne;Robinson, James T.;Pajtler, Kristian W.;Milde, Till;Jaeger, Natalie;Fiesel, Petra;Morgan, Ling;Sridhar, Sunita;Coufal, Nicole G.;Levy, Michael;Malicki, Denise;Hobbs, Charlotte;Kingsmore, Stephen;Nahas, Shareef;Snuderl, Matija;Crawford, John;Wechsler-Reya, Robert J.;Davidson, Tom Belle;Cotter, Jennifer;Michaiel, George;Fleischhack, Gudrun;Mundlos, Stefan;Schmitt, Anthony;Carter, Hannah;Michealraj, Kulandaimanuvel Antony;Kumar, Sachin A.;Taylor, Michael D.;Rich, Jeremy;Buchholz, Frank;Mesirov, Jill P.;Pfister, Stefan M.;Ay, Ferhat;Dixon, Jesse R.;Kool, Marcel;Chavez, Lukas
室管膜瘤是一种大脑或脊髓的肿瘤。室管膜瘤最常见和最具侵袭性的两个分子群是幕上ZFTA融合相关的和后颅窝室管膜瘤A组。在这两组中，肿瘤主要发生在幼儿，治疗后经常复发。尽管这些疾病背后的分子机制最近已经被发现，但它们仍然很难被靶向，迫切需要创新的治疗方法。在这里，我们使用全基因组染色体构象捕获(Hi-C)，辅以CTCF和H3K27ac芯片序列，以及原发和复发性室管膜瘤的基因表达和DNA甲基化分析，以确定与异常基因表达相关的染色体构象和调控机制。特别是，我们观察到由结构变体、基团特定的3D染色质环以及CTCF绝缘体被DNA超甲基化取代所导致的新的拓扑相关结构域(‘neo-TADS’)的形成。通过抑制实验，我们验证了这些3D基因组构象所涉及的基因对于患者来源的室管膜瘤模型以组特异性方式生存是必不可少的。因此，这项研究扩大了我们通过3D基因组构象揭示肿瘤依赖基因的能力，即使在缺乏靶向基因改变的肿瘤中也是如此。室管膜瘤是一种脑或脊髓的肿瘤，有两种最常见和侵袭性的类型，主要发生在儿童。在这里，作者使用3D基因组学和表观基因组学来揭示儿童侵袭性室管膜瘤的靶点。
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations. Ependymoma is a tumor of the brain or spinal cord with the two most common and aggressive types mainly occurring in children. Here the authors employ 3D genomics and epigenomics to reveal targets for aggressive ependymoma tumors in children.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
在神经元分化过程中，Corest1和Corest2与LSD1和HDAC1/2的表达降低。
影响因子：
3.7
作者：
Sáez JE;Gómez AV;Barrios ÁP;Parada GE;Galdames L;González M;Andrés ME
通讯作者：
Andrés ME
影响因子：
64.5
作者：
Lupiáñez DG;Kraft K;Heinrich V;Krawitz P;Brancati F;Klopocki E;Horn D;Kayserili H;Opitz JM;Laxova R;Santos-Simarro F;Gilbert-Dussardier B;Wittler L;Borschiwer M;Haas SA;Osterwalder M;Franke M;Timmermann B;Hecht J;Spielmann M;Visel A;Mundlos S
通讯作者：
Mundlos S
影响因子：
14.9
作者：
Kumar R;Sobhy H;Stenberg P;Lizana L
通讯作者：
Lizana L
影响因子：
23.9
作者：
Lathia JD;Gallagher J;Heddleston JM;Wang J;Eyler CE;Macswords J;Wu Q;Vasanji A;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN