RNA-mediated Feedback Control of Oncogenic Transcription

项目总结/摘要 核内动态的无膜体大量聚集的凝聚转录模型 许多转录成分最近被描述，提供了一个新的框架，以解决 神秘的转录。早期对复合凝聚层中RNA的研究表明，RNA可以具有阳性表达， 和对蛋白质浓缩物的负面影响，并可控制基因表达。初步 数据证实了这样的预测，即低水平的RNA，就像那些存在于早期转录起始过程中的RNA， 用助活化剂Mediator刺激冷凝物，并在更高水平下溶解它们。转录 失调是癌症的标志，但致癌转录如何维持高水平的表达， 仍然没有解决。可能是RNA介导的缩合物的行为在癌细胞中发生了改变。 细胞，也许还有像MYC这样的关键癌基因在这种行为中起着尚未描述的作用 以前因此，这项提议将检验致癌蛋白过量水平补偿 通过使转录浓缩物更耐溶解来提高RNA产量。的驱动因素 肿瘤发生和转移可能对转录失调有物理化学作用， 这是在转录的凝聚模型出现之前所预期的。为了验证这一假设， 包括将表征致癌浓缩物和评估致癌蛋白的能力， 使其稳定在癌细胞中。作为本提案的一部分，相关培训将包括加强和学习 在超分辨率显微镜，细胞工程，蛋白质生物化学和癌症生物学的新技能。的 这一提议的结果将提供直接证据，表明由生物化学产物介导的生物物理现象， 转录，调节正常和恶性状态下的基因表达。他们将提供潜在的新路线 开发针对癌症中难以靶向的转录因子和转录依赖性的疗法。

PROJECT SUMMARY/ABSTRACT Condensate models of transcription in which dynamic, membraneless bodies in the nucleus concentrate large numbers of transcriptional components have recently been described, providing a new framework to solve mysteries in transcription. Early studies of RNA in complex coacervates revealed that RNA can have positive and negative effects on proteinaceous condensates and may operate to control gene expression. Preliminary data confirms the prediction that RNAs at low levels, like those present during early transcription initiation, will stimulate condensates with the coactivator Mediator, and at higher levels, dissolve them. Transcriptional dysregulation is a hallmark of cancer, but how oncogenic transcription maintains high levels of expression remains unresolved. It is possible that the RNA-mediated behavior of condensates is altered in cancerous cells, and perhaps key oncogenes like MYC have a function in this behavior that has not been described before. Thus, this proposal will test the hypothesis that excess levels of oncogenic proteins compensate for higher RNA production by making transcriptional condensates more resistant to dissolution. The drivers of oncogenesis and metastasis may have a physicochemical effect on transcriptional dysregulation that was not anticipated before the advent of the condensate model of transcription. To test this hypothesis, the proposal includes aims that will characterize oncogenic condensates and evaluate the ability of oncogenic proteins to stabilize them in cancer cells. As part of this proposal, relevant training will include strengthening and learning new skills in super-resolution microscopy, cellular engineering, protein biochemistry, and cancer biology. The results from this proposal will provide direct evidence that biophysical phenomenon, mediated by the product of transcription, regulate gene expression in normal and malignant states. They will provide potential new routes to develop therapies against hard-to-target transcription factors and transcriptional dependencies in cancer.