RNA-mediated Feedback Control of Oncogenic Transcription

项目摘要/摘要 核内动态的、无膜性小体集中大量转录的凝聚态转录模型 最近描述了许多转录成分，提供了一个新的框架来解决 抄写中的谜团。早期对复杂凝聚体中的RNA的研究表明，RNA可以具有阳性 以及对蛋白质凝聚物的负面影响，并可能控制基因表达。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启动过程中的RNA一样，将 用助活剂调节剂刺激凝析油，并在更高的水平上溶解它们。转录的 调控失调是癌症的一个标志，但致癌基因转录如何维持高水平的表达 仍然悬而未决。在癌症中，冷凝物的RNA介导的行为可能会发生改变 细胞，也许还有像MYC这样的关键癌基因，在这种行为中具有尚未被描述的功能 在此之前。因此，这一提议将检验这样一种假设，即过量的致癌蛋白水平弥补了 通过使转录缩合物更耐溶解而产生更高的RNA。的驱动因素 肿瘤的发生和转移可能对转录失调有物理化学影响，而不是 在转录的凝聚态模型出现之前就已经预料到了。为了检验这一假设，该提案 包括将表征致癌冷凝物并评估致癌蛋白 让它们稳定在癌细胞中。作为这项提议的一部分，相关培训将包括加强和学习 在超分辨显微镜、细胞工程、蛋白质生物化学和癌症生物学方面的新技能。这个 这一提议的结果将提供直接证据，证明生物物理现象是由 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的治疗方法。

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.