转录组学分析从功能上绘制了EWS/FLI的内在紊乱结构域,并揭示了肿瘤发生的新的转录依赖性。

Q2 Biochemistry, Genetics and Molecular Biology
Emily R Theisen, Kyle R Miller, Iftekhar A Showpnil, Cenny Taslim, Kathleen I Pishas, Stephen L Lessnick
{"title":"转录组学分析从功能上绘制了EWS/FLI的内在紊乱结构域,并揭示了肿瘤发生的新的转录依赖性。","authors":"Emily R Theisen,&nbsp;Kyle R Miller,&nbsp;Iftekhar A Showpnil,&nbsp;Cenny Taslim,&nbsp;Kathleen I Pishas,&nbsp;Stephen L Lessnick","doi":"10.18632/genesandcancer.188","DOIUrl":null,"url":null,"abstract":"<p><p>EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and the carboxy-terminal FLI portion contains an ETS DNA-binding domain. EWS/FLI acts as an aberrant transcription factor, orchestrating a complex mix of gene activation and repression, from both high affinity ETS motifs and repetitive GGAA-microsatellites. Our overarching hypothesis is that executing multi-faceted transcriptional regulation requires EWS/FLI to use distinct molecular mechanisms at different loci. Many attempts have been made to map distinct functions to specific features of the EWS domain, but described deletion mutants are either fully active or completely \"dead\" and other approaches have been limited by the repetitive and disordered nature of the EWS domain. Here, we use transcriptomic approaches to show an EWS/FLI mutant, called DAF, previously thought to be nonfunctional, displays context-dependent and partial transcriptional activity but lacks transforming capacity. Using transcriptomic and phenotypic anchorage-independent growth profiles of other EWS/FLI mutants coupled with reported EWS/FLI localization data, we have mapped the critical structure-function requirements of the EWS domain for EWS/FLI-mediated oncogenesis. This approach defined unique classes of EWS/FLI response elements and revealed novel structure-function relationships required for EWS/FLI activation at these response elements.</p>","PeriodicalId":38987,"journal":{"name":"Genes and Cancer","volume":"10 1-2","pages":"21-38"},"PeriodicalIF":0.0000,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420793/pdf/","citationCount":"14","resultStr":"{\"title\":\"Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.\",\"authors\":\"Emily R Theisen,&nbsp;Kyle R Miller,&nbsp;Iftekhar A Showpnil,&nbsp;Cenny Taslim,&nbsp;Kathleen I Pishas,&nbsp;Stephen L Lessnick\",\"doi\":\"10.18632/genesandcancer.188\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and the carboxy-terminal FLI portion contains an ETS DNA-binding domain. EWS/FLI acts as an aberrant transcription factor, orchestrating a complex mix of gene activation and repression, from both high affinity ETS motifs and repetitive GGAA-microsatellites. Our overarching hypothesis is that executing multi-faceted transcriptional regulation requires EWS/FLI to use distinct molecular mechanisms at different loci. Many attempts have been made to map distinct functions to specific features of the EWS domain, but described deletion mutants are either fully active or completely \\\"dead\\\" and other approaches have been limited by the repetitive and disordered nature of the EWS domain. Here, we use transcriptomic approaches to show an EWS/FLI mutant, called DAF, previously thought to be nonfunctional, displays context-dependent and partial transcriptional activity but lacks transforming capacity. Using transcriptomic and phenotypic anchorage-independent growth profiles of other EWS/FLI mutants coupled with reported EWS/FLI localization data, we have mapped the critical structure-function requirements of the EWS domain for EWS/FLI-mediated oncogenesis. This approach defined unique classes of EWS/FLI response elements and revealed novel structure-function relationships required for EWS/FLI activation at these response elements.</p>\",\"PeriodicalId\":38987,\"journal\":{\"name\":\"Genes and Cancer\",\"volume\":\"10 1-2\",\"pages\":\"21-38\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2019-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420793/pdf/\",\"citationCount\":\"14\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genes and Cancer\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.18632/genesandcancer.188\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genes and Cancer","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.18632/genesandcancer.188","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 14

摘要

EWS/FLI是驱动Ewing肉瘤的病理融合癌蛋白。氨基末端EWS部分协调转录调控,羧基末端FLI部分包含一个ETS dna结合域。EWS/FLI作为一种异常转录因子,从高亲和力的ETS基序和重复的ggaa微卫星中协调基因激活和抑制的复杂组合。我们的首要假设是,执行多方面的转录调控需要EWS/FLI在不同的位点上使用不同的分子机制。已经有许多尝试将不同的功能映射到EWS结构域的特定特征,但是所描述的缺失突变体要么完全活跃,要么完全“死亡”,并且其他方法受到EWS结构域的重复和无序性质的限制。在这里,我们使用转录组学方法来显示EWS/FLI突变,称为DAF,以前被认为是无功能的,显示上下文依赖和部分转录活性,但缺乏转化能力。利用其他EWS/FLI突变体的转录组学和表型锚定非依赖性生长谱,结合已报道的EWS/FLI定位数据,我们绘制了EWS结构域在EWS/FLI介导的肿瘤发生中的关键结构-功能要求。该方法定义了EWS/FLI反应元件的独特类别,并揭示了在这些反应元件上激活EWS/FLI所需的新型结构-功能关系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.

Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.

Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.

Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.

EWS/FLI is the pathognomic fusion oncoprotein that drives Ewing sarcoma. The amino-terminal EWS portion coordinates transcriptional regulation and the carboxy-terminal FLI portion contains an ETS DNA-binding domain. EWS/FLI acts as an aberrant transcription factor, orchestrating a complex mix of gene activation and repression, from both high affinity ETS motifs and repetitive GGAA-microsatellites. Our overarching hypothesis is that executing multi-faceted transcriptional regulation requires EWS/FLI to use distinct molecular mechanisms at different loci. Many attempts have been made to map distinct functions to specific features of the EWS domain, but described deletion mutants are either fully active or completely "dead" and other approaches have been limited by the repetitive and disordered nature of the EWS domain. Here, we use transcriptomic approaches to show an EWS/FLI mutant, called DAF, previously thought to be nonfunctional, displays context-dependent and partial transcriptional activity but lacks transforming capacity. Using transcriptomic and phenotypic anchorage-independent growth profiles of other EWS/FLI mutants coupled with reported EWS/FLI localization data, we have mapped the critical structure-function requirements of the EWS domain for EWS/FLI-mediated oncogenesis. This approach defined unique classes of EWS/FLI response elements and revealed novel structure-function relationships required for EWS/FLI activation at these response elements.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Genes and Cancer
Genes and Cancer Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.90
自引率
0.00%
发文量
6
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信