A systems approach to understand the origin of transcriptional bursting

基因相同的细胞，在相同的环境中，往往表现得非常不同。这在转录中很明显，在单个细胞中发现的mRNA通常有很大的变化。人们对这种转录噪声知之甚少，尤其是在哺乳动物细胞中。理解和控制这种噪音对合成生物学非常有意义，因为这种噪音使合成基因网络不可预测和不可靠。特别有趣的是转录爆发现象，这是当基因在“关闭”状态和“打开”状态之间切换时，转录只发生在“打开”状态。这导致了基因表达的爆发。我的研究将解决这个问题——转录爆发的起源是什么？本研究将结合成像、基因工程、高通量测序、生物信息学和模型拟合来回答这个问题。更具体地说;通过干扰启动子与基因3′端之间的相互作用和干扰介质/RNA聚合酶II凝聚。该项目的预期结果将是我们对哺乳动物细胞转录变异性的理解的重大进步，特别是DNA相互作用和聚合酶凝聚物如何影响这一点。该项目还将提供控制生物噪声的新方法，这是合成生物学应用的重要知识。

Genetically identical cells, in identical environments often behave very differently to each other. This is clearly evident in transcription which often has large variations of mRNA in that are found in individual cells. This transcriptional noise is poorly understood, especially in mammalian cells. Understanding, and controlling this noise is of great interest to synthetic biology as this noise makes synthetic genetic networks unpredictable and unreliable.Of particular interest is the phenomena of transcriptional bursting, this is when a gene switches between an 'off' state and an 'on' state, where transcription only occurs in the 'on' state. This results in bursts of expression of a gene. My research will address the question - what is the origin of transcriptional bursting?This research will answer the question by combining imaging, genetic engineering, high throughput sequencing, bioinformatics and model fitting. More specifically; by perturbing interactions between the promotor and the 3' ends of genes and perturbing mediator/RNA polymerase II condensates.The projected outcomes of this project would be a significant advance in our understanding of transcriptional variability in mammalian cells, in particular how DNA interactions and polymerase condensates influence this. The project will also provide new ways to control biological noise, vital knowledge for synthetic biology applications.