A systems approach to understand the origin of transcriptional bursting

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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.