在单分子分辨率下对内源转录因子枢纽的动态调节
bioRxiv : the preprint server for biology
|February 9, 2026
概括
转录因子 (TF) 形成基因激活必需的动态枢纽. 这项研究揭示了Ewing肉瘤中的EWS::FLI1枢纽,显示了它们独特的形成,线粒作用和对治疗化合物的敏感性.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物物理学的生物物理.
背景情况:
- 细胞转录因子 (TFs) 通过多价值相互作用在特定的基因组位点组装成高度枢纽.
- 这些TF枢纽对于转录激活至关重要,但它们的生物物理性质仍然不太清楚.
- 调查内源性TF枢纽动态需要先进的成像技术在本地细胞环境.
研究的目的:
- 为了研究Ewing肉瘤细胞中致癌融合TF EWS::FLI1的动态行为和调节.
- 描述内源性 EWS::FLI1 中枢的形成,溶解和线粒作用.
- 评估治疗化合物的对EWS::FLI1枢纽形成和定位的影响.
主要方法:
- 通过CRISPR/Cas9进行基因组编辑,用于内源性TF修饰.
- 先进的定量细胞成像,包括单分子显微镜.
- 对TF枢纽形成,溶解和分子相互作用的动态分析.
主要成果:
- 内生 EWS::FLI1 形成动态的,分衍射极限枢纽,与液态-液态相分离不同.
- EWS::FLI1枢纽形成是一种在父蛋白中不存在的新形态行为.
- EWS::FLI1在线粒体书签中发挥作用,在线粒体分裂过程中,枢纽会溶解.
- 新生RNA破坏了EWS::FLI1枢纽的稳定,而LY2835219和trabectedin改变了EWS::FLI1的核分布.
结论:
- EWS::FLI1枢纽组装和调节的特点是前所未有的分辨率.
- 这项研究揭示了Ewing肉瘤中LY2835219和trabectedin的治疗潜力.
- 开发的方法使未来能够在各种蜂环境中对功能TF集线器进行表征.
相关概念视频
02:16Transcription Factors
82.8K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
82.8K
02:23Master Transcription Regulators
7.8K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.8K
02:23Master Transcription Regulators
2.8K
2.8K
01:23Negative Regulator Molecules
38.6K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.6K
02:13Cooperative Binding of Transcription Regulators
7.4K
Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome. Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
7.4K
02:35Transcription Elongation Factors
14.0K
Transcription elongation is a dynamic process that alters depending upon the sequence heterogeneity of the DNA being transcribed. Hence, it is not surprising that the elongation complex's composition also varies along the way while transcribing a gene.
The transcription elongation is regulated via pausing of RNA polymerase on several occasions during transcription. In bacteria, these halts are necessary because the transcription of DNA into mRNA is coupled to the translation of that mRNA...
The transcription elongation is regulated via pausing of RNA polymerase on several occasions during transcription. In bacteria, these halts are necessary because the transcription of DNA into mRNA is coupled to the translation of that mRNA...
14.0K