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Title: Transcriptome-wide study of the role of arginine methylation on E2F1
Author: Roworth, Alice Poppy
ISNI:       0000 0004 7232 723X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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The transcription factor E2F1 can have diverse phenotypic effects on the cell, from stimulating cell cycle progression and proliferation, to inducing apoptosis. These seemingly opposite effects are regulated by a multiplicity of post-translational modifications. Three sites of arginine methylation have been shown to cause a switch in E2F1 function, with PRMT5 mediated symmetric dimethylation at R111/113 associated with a proliferative outcome and asymmetric dimethylation at R109 by PRMT1 resulting in apoptosis. Importantly, these sites of arginine methylation by PRMT1 or PRMT5 were shown to be mutually exclusive, eliciting an either/or response. Furthermore, a reader for the R111/113Me2s mark was found to be the tudor-domain containing transcription co-activator and RNA binding protein p100-TSN. In this study we have used genome-wide sequencing techniques to explore the role of arginine methylation on E2F1 and identify how it is exerting these diverse effects. We found that, although there were few transcription level changes upon expression of an R111/113K mutant derivative compared to the wild-type expressing cells, these cells exhibited dramatic changes at the RNA isoform level across many E2F1 target genes, including increased levels of proapoptotic isoforms of p73 and BCL-X. Interestingly, the vast majority of these differentially spliced genes did not overlap with the genes showing transcription level changes, suggesting a new role for E2F1 to modulate target gene expression via RNA processing. Furthermore, we discovered that E2F1 can bind to nascent RNA via its interaction with p100-TSN and that this complex is spliceosome associated. Additionally, E2F1 can influence the RNA isoforms of p73 and BCL-X found interacting with p100-TSN. Thus, we present a model suggesting that E2F1 may be directly impacting on RNA processing by aiding assembly of splicing components as transcription occurs.
Supervisor: Coutts, Amanda S. ; La Thangue, Nicholas B. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available