Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.
Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.
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系统的多组学细胞系分析揭示了尤文肉瘤融合癌基因介导的基因调控的原理。
DOI：
10.1016/j.celrep.2022.111761
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发表时间：
2022-12-06
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
尤文肉瘤(EWS)的特征是EWSR1-ETS融合转录因子将多态的GGAA微卫星(MSats)转化为有效的新增强子。虽然缺乏额外的突变使EWS成为研究显性融合癌基因和新增强子之间合作原理的真正模型，但这受到有限数量的良好表征的模型的阻碍。在这里，我们介绍尤文肉瘤细胞系图谱(ESCLA)，包括18个具有可诱导EWSR1-ETS基因敲除的细胞系的全基因组、DNA甲基化、转录组、蛋白质组和染色质免疫沉淀测序(CHIP-SEQ)数据。ESCLA显示了数百个EWSR1-ETS靶标，EWSR1-ETS偏好的GGAA mSats的性质，以及EWSR1-ETS介导的基因调控的假定间接模式，收敛于特定但可塑的EWS签名的二元性。我们确定异质性调节的EWSR1-ETS靶点作为潜在的预测EWS的生物标志物。我们免费提供的ESCLA(http://r2platform.com/escla/))是EWS研究的丰富资源，并突出了全面数据集的力量，以揭示嵌合转录因子对异质基因调控的原理。Orth et al.利用多组学分析研究儿科癌症尤文肉瘤的异质性。他们提供了18个细胞系的综合数据集，以说明致病原融合癌蛋白与多态调控DNA元件的异质性结合，这可能有助于预后相关基因的可变表达。
Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors. Orth et al. leverage multi-omics analyses to study heterogeneity in the pediatric cancer Ewing sarcoma. They present a comprehensive dataset of 18 cell lines to illustrate heterogeneous binding of pathognomonic fusion oncoproteins to polymorphic regulatory DNA elements, which may contribute to the variable expression of prognostically relevant genes.
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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
影响因子：
8
作者：
Cidre-Aranaz, F.;Gruenewald, T. G. P.;Alonso, J.
通讯作者：
Alonso, J.
影响因子：
10.5
作者：
Boulay G;Volorio A;Iyer S;Broye LC;Stamenkovic I;Riggi N;Rivera MN
通讯作者：
Rivera MN
影响因子：
50.3
作者：
Adane B;Alexe G;Seong BKA;Lu D;Hwang EE;Hnisz D;Lareau CA;Ross L;Lin S;Dela Cruz FS;Richardson M;Weintraub AS;Wang S;Iniguez AB;Dharia NV;Conway AS;Robichaud AL;Tanenbaum B;Krill-Burger JM;Vazquez F;Schenone M;Berman JN;Kung AL;Carr SA;Aryee MJ;Young RA;Crompton BD;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
5.8
作者：
Aryee, Martin J.;Jaffe, Andrew E.;Irizarry, Rafael A.
通讯作者：
Irizarry, Rafael A.