Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770808
Title: Study of the dynamics of gene expression by mathematical modelling and systems approaches
Author: Brown, Thomas
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Abstract:
Transcription by RNA Polymerase II (RNA PolII) is a fundamental process at the heart of gene expression, defining the phenotypes of cells. Transcription of genes does not exist in isolation, but occurs through a complex environment of DNA wrapped around chromatin, with many factors affecting the surrounding environment and association with the polymerase. The process of transcription is more complex than perhaps originally thought, with a number of factors affecting individual steps of the process of reading the DNA template. Rather than thinking of a gene as simply being on or off, the expression of a gene is regulated and fine-tuned by the modifications to the chromatin landscape, cross-talk between the chromatin and the elongation complex, pervasive non-coding transcription and the association of factors with the polymerase. By developing mathematical models of the transcription and RNA processing networks, we determine the effects of these factors on establishing the dynamics of native gene expression. Constructing best-fit models and identifying key parameters which dictate the changes to quantitative data upon genetic intervention, we identify a feedback mechanism to accommodate for changes in the rates of transcript production and polymerase stalling as a predictor of the processivity of individual genes. A number of factors are shown to control the speed and processivity of polymerase in Saccharomyces cerevisiae and HeLa cells, establishing a network of cooperative and antagonistic interactions with the RNA PolII complex. This work suggests that the dynamics of transcription are gene-specific, with the chromatin landscape and the polymerase-associating factors unique to each locus in the mammalian genome.
Supervisor: Angel, Andrew ; Mellor, Jane Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.770808  DOI: Not available
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