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Title: The role of enhancers in regulating the transcription cycle
Author: Larke, Martin
ISNI:       0000 0004 7966 1927
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Enhancers are key determinants in the spatiotemporal control of gene expression which underlies cellular differentiation and disease; however, the dominant mechanisms through which they exert their effects on genes remain poorly understood. In order to achieve fine control over nascent transcript levels, transcription is highly regulated at many stages. It has been suggested that enhancers may act on many specific stages in transcription to modulate transcript production. The idea that initiation of transcription is the principal barrier in achieving changes in gene expression has been challenged by the discovery of promoter proximal pausing of RNA polymerase II (Pol 2 pausing) at the majority of protein coding genes in addition to further downstream regulatory steps. In this thesis I sought to determine the predominant mechanism by which enhancers bring about differential gene expression in vivo by examining knockout models of well-defined enhancers at the alpha and beta globin gene clusters. Using a wide variety of complementary methodologies, I demonstrate that these two enhancer clusters promote transcription initiation whilst having minimal effects on downstream transcriptional kinetics. In addition, I build on these findings to show that genome-wide differential transcription initiation best correlates with differential gene expression and is likely the predominant regulatory step in transcription. Pol2 pausing is detectable genome-wide but scales according to initiation frequency suggesting this process is an inherent kinetic property of mammalian promoters, but its role in gene regulation may be less significant than previously thought. This study highlights the role that enhancers play in regulation of specific stages in transcription to achieve tissue-specific gene expression. These findings may be applicable to the broader study of metazoan transcription, given the highly conserved nature of transcriptional mechanisms and will enable a better understanding of how eukaryotic gene expression is altered development and disease.
Supervisor: Hughes, Jim ; Higgs, Doug Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available