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Title: Environmental and genetic effects on gene expression and regulation
Author: Morrison, Faer Samara
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2013
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Regulation of gene expression is under tight control under normal circumstances and aberrant expression of genes is 'associated with complex diseases such as Type 2 Diabetes (T2D), Type 1 Diabetes (T1D) and autoimmune diseases. Posttranscriptional mechanisms of gene expression regulation, including alternative mRNA splicing, mRNA stability, and miRNA-mediated regulation of gene expression can be influenced by different factors, including environmental factors and genetic variation. A pathological microenvironment, or genetic variation that increases susceptibility to developing complex diseases (risk variants), may alter regulation of gene expression, potentially via these post-transcriptional mechanisms. The aim of this thesis is to investigate both the effect of the T2D microenvironment on gene expression, as well as the direct effect of genetic variation on post-transcriptional mechanisms of gene expression regulation in autoimmune diseases. Features of the T2D microenvironment, such as hyperglycemia, hyperlipidemia, and increased reactive oxygen species production have been shown to alter gene expression. In chapters 3, 4, and 5, I investigated if the T2D microenvironment altered expression of genes that may be important in T2D pathogenesis and progression. In Chapter 3, I analyzed the expression of genes involved in oxidative metabolism in a rodent pancreatic beta cell line in response to hypo- I hyperglycemia-induced reactive oxygen species (ROS) production. I observed that although the expression of several genes was influenced by increasing glycemia, these changes were probably not mediated by increased ROS production. In chapters 4 and 5, I analyzed the expression of genes in loci that have been ~ associated with T20 susceptibility by genome wide association studies (GWAS) in T20 islets as well as in insulin-dependent tissues. I found widespread deregulation of the expression of these genes in these tissues. The loci identified by GWAS to alter disease susceptibility can span hundreds of genes and identifying the causal variant or variants is a difficult challenge. The Encyclopedia of DNA Elements (ENCODE) project has recently validated the importance of non-coding genomic regions in regulation of gene expression. In chapters 6 and 7, I investigated the effect of single nucleotide polymorph isms (SNPs) that have been associated with autoimmune disease susceptibility, on alternative mRNA splicing, and 3'UTR-mediated regulation of gene expression. I identified changes to the alternative splicing of a gene within the important 17q12- 21 asthma! autoimmune disease locus, that were associated with a splice site SNP, as well as identifying 3'UTR SNPs that may alter miRNA-mediated regulation of the expression of their host genes. I have identified widespread deregulation of gene expression in the T20 microenvironment, as well as describing examples of how SNPs can alter posttranscriptional mechanisms of gene expression regulation, such as alternative splicing and 3'UTR-mediated regulation. The role of environmental factors, such as toxin exposure, diet and other lifestyle factors are important for how an individual's genes are expressed. It is now becoming increasingly apparent that gene effects cannot be looked at in isolation, as it is the interaction between genetics (such as the effect of SNPs) and environmental influence (such as the effects of glycemia) on expression of genes that determines an individual's phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available