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Title: Investigating the role of alternative polyadenylation in neuronal differentiation and neurodegeneration
Author: Patel, Radhika
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Over 70% of human genes can undergo alternative polyadenylation (APA), whereby they utilise different polyadenylation (poly(A)) sites found in the 3'UTR (3'UTR-APA) or in the upstream coding region of the gene (upstream-APA). The 3'UTR harbours regulatory cis-elements which can mediate the stability, translatability and localisation of the mRNA. Therefore, modulating 3'UTR length through APA can affect downstream gene expression. The UTR landscape can be modified through altered poly(A) site choice during transcription, or in a post-transcriptional manner, via interaction with miRNAs or RNA binding proteins. Global shifts in UTR length have been identified in different tissues and cellular states. Using a combination of molecular biology and bioinformatics approaches, this thesis assesses changes in APA profiles regulated by transcriptional and post-transcriptional APA during neuronal differentiation, in neurodegeneration and in cellular stress. The BE(2)-M17 neuroblastoma cell line was used to model neuronal differentiation. Here, the trend to UTR lengthening in differentiation was attributed primarily to post-transcriptional not transcriptional APA regulation. APA in neurodegeneration was assessed using an in vitro model and publicly available RNA-seq datasets were bioinformatically interrogated to assess UTR length changes in Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis. While global APA changes were not observed, genes associated with pathophysiological pathways were identified, highlighting the important role of APA mediated gene expression in neurodegenerative diseases. Exposure to cold shock and hypoxia showed differential APA regulation. Interestingly, moderate hypothermia caused a trend to 3'UTR lengthening, even in combination with other stress inducers. These UTR-lengthened genes exhibited binding sites for proteins that associate in stress granules. Therefore, APA regulation may contribute to the aggregation of mRNAs in stress granules during stress conditions. In conclusion, this thesis identifies an unprecedented role of post-transcriptional regulation of the UTR landscape, and identifies physiologically relevant genes regulated by APA during the changing cellular environment.
Supervisor: Furger, Andre M. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available