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Title: Transcription and three-dimensional organisation of the genome
Author: Clay, I.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2011
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By sequencing nuclear RNA and active RNA polymerase II bound chromatin, I demonstrate that a large variation is observed in the relative amount of RNA and polymerase associated with annotated genes. Similar to the idea of promoter proximal stalling, particular patterns of polymerase occupancy are observed to associate with genes which though highly polymerase bound, produce little RNA. Other patterns are observed on genes which produce high levels of RNA compared to the amount of polymerase and evidence is presented that this pattern may indicate ‘gene looping’. I also show that these data can be used to identify putative enhancers and long non-coding RNAs. These methods provide a simple method for trasnscriptome characterisation. Using chromatin interaction analysis using paired end sequencing (ChIA-PET), I then investigated the existence, extent and significance of functional relationships between interacting regions of the transcribed genome. The interactions between RNA polymerase II bound regions of the genome form a wide-ranging, highly reproducible, scale-free network of non-random connections between linked and unlinked loci. I validate that these interactions accurately capture genome organisation at gross and fine resolution and go on to show that widespread interactions occur between co-functional and co-regulated genes. These interactions may be a generally applicable concept for the co-ordination of gene expression, not only within cellular processes, but between multiple systems. Finally I contribute to the development of a single cell HiC methodology which will be used to address the question of whether the population-wide concepts of genome organisation can be applied to any given single cell in that population. These results explore and describe many aspects of transcriptional regulation and highlights the role that three-dimensional genome organisation plays in this multifaceted process.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available