Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis.
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis.
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使用转录组分析绘制无序致癌转录因子的结构-功能关系。
DOI：
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
E. Theisen
中科院分区：
文献类型：
--
作者：
Iftekhar A. Showpnil;K. R. Miller;C. Taslim;K. I. Pishas;S. Lessnick;E. Theisen
许多癌症的特征是染色体易位，导致致癌融合转录因子的表达。通常，这些蛋白质含有与另一种蛋白质的DNA结合结构域（DBD）融合的固有无序结构域（IDD），并协调广泛的转录变化以促进恶性肿瘤。这些融合通常是它们引起的癌症中唯一的复发性基因组畸变，使它们成为有吸引力的治疗靶点。然而，靶向致癌转录因子需要更好地理解低复杂性IDDs在其功能中发挥的机制作用。EWSR 1的N端结构域是一个IDD，参与多种致癌融合转录因子，包括EWS/FLI、EWS/ATF和EWS/WT 1。在这里，我们使用RNA测序研究的EWS结构域的EWS/FLI在尤文肉瘤的转录功能的重要结构特征。首先进行shRNA介导的尤文肉瘤细胞内源性融合物的耗竭，并与多种EWS突变体构建体的异位表达配对。然后使用RNA测序来分析表达这些构建体的细胞的转录组，以表征与EWS结构域中的突变相关的功能缺陷。通过整合转录组学分析与先前发表的信息EWS/FLI DNA结合基序，基因组定位，以及转化能力的功能测定，我们能够确定EWS/FLI的结构特征的肿瘤发生的重要性，并定义一组新的EWS/FLI靶基因尤文肉瘤的关键。本文展示了使用RNA测序作为一种方法来映射的致癌转录因子的内在无序结构域的结构-功能关系。
Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with the DNA-binding domain (DBD) of another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets. However, targeting oncogenic transcription factors requires a better understanding of the mechanistic role that low-complexity, IDDs play in their function. The N-terminal domain of EWSR1 is an IDD involved in a variety of oncogenic fusion transcription factors, including EWS/FLI, EWS/ATF, and EWS/WT1. Here, we use RNA-sequencing to investigate the structural features of the EWS domain important for transcriptional function of EWS/FLI in Ewing sarcoma. First shRNA-mediated depletion of the endogenous fusion from Ewing sarcoma cells paired with ectopic expression of a variety of EWS-mutant constructs is performed. Then RNA-sequencing is used to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain. By integrating the transcriptomic analyses with previously published information about EWS/FLI DNA binding motifs, and genomic localization, as well as functional assays for transforming ability, we were able to identify structural features of EWS/FLI important for oncogenesis and define a novel set of EWS/FLI target genes critical for Ewing sarcoma. This paper demonstrates the use of RNA-sequencing as a method to map the structure-function relationship of the intrinsically disordered domain of oncogenic transcription factors.
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影响因子：
50.3
作者：
Riggi N;Knoechel B;Gillespie SM;Rheinbay E;Boulay G;Suvà ML;Rossetti NE;Boonseng WE;Oksuz O;Cook EB;Formey A;Patel A;Gymrek M;Thapar V;Deshpande V;Ting DT;Hornicek FJ;Nielsen GP;Stamenkovic I;Aryee MJ;Bernstein BE;Rivera MN
通讯作者：
Rivera MN
多个结构域介导尤文氏肉瘤 EWS/FLI-1 融合基因的转化。
DOI：
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发表时间：
1995
期刊：
Oncogene.
影响因子：
--
作者：
Lessnick,SL;Braun,BS;Denny,CT;May,WA
通讯作者：
May,WA
影响因子：
64.8
作者：
Groebner, Susanne N.;Worst, Barbara C.;Pfister, Stefan M.
通讯作者：
Pfister, Stefan M.
影响因子：
5.7
作者：
Leach, Benjamin I.;Kuntimaddi, Aravinda;Schmidt, Charles R.;Cierpicki, Tomasz;Johnson, Stephanie A.;Bushweller, John H.
通讯作者：
Bushweller, John H.
癌症基因是由罕见的染色体重排而不是癌基因激活产生的。
DOI：
10.1007/bf02934512
发表时间：
1987
期刊：
Medical oncology and tumor pharmacotherapy
影响因子：
--
作者：
Duesberg,PH
通讯作者：
Duesberg,PH