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A systems biology study of alternative splicing regulations and functions

University of British Columbia

Alternative splicing is highly appreciated as a major contributor to cellular complexity, and its dysregulation has been associated to several diseases. Despite being the focus of numerous studies in recent years, there remains much unknown about functions and regulations of alternative splicing in mammalian systems. Here, I take a systems biology approach to study alternative splicing using high-throughput sequencing data. In Chapter 2, I use tissue-specific high-throughput libraries of Drosophila melanogaster to explore the potential inter-relation of RNA editing and alternative splicing. I first develop a pipeline to accurately detect editing events. Next, I find regions where editing and splicing are likely to influence each other, and report conserved RNA structures that can mediate the inter-relation. In Chapter 3, I study functions of Cyclin dependent kinase 12 (CDK12) using human cell line data. I show that CDK12 influences the differential usage of alternative last exon. Additionally, the results demonstrate that CDK12 modulates the expression of DNA damage response genes, and increases the tumorigenicity of breast cancer cells by down-regulating the long isoform of DNAJB6 gene. Finally, in chapter 4, I first present a review of methods that search for underlying mechanisms explaining variations between high-throughput measurements of two biological conditions. Next, I introduce our RNA-seq data derived from progressively inhibiting splicing-related proteins at multiple concentrations of pharmaceuticals, and I discuss how the reviewed methods should be adopted to benefit most from our type of data. Our systems biology research provides new insights on how the studied components of the splicing machinery contribute to splicing functions and regulations, and these findings can help to improve our understanding of related diseases.

Text

2017-12-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/61967

Bioinformatics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/