Comparativegenome-wide DNA methylationstudies of healthyhumantissues and non-smallcelllungcancertisuse
Kaie Lokk
Methylated cytosineshave a crucial role in mammalian development, and the proportion of methylated CpG sites can vary greatly over a genome.As DNA methylation is vital for the normal functioning of organism, changes in the epigenome can account for individual differences in drug responses or the incidence of severe diseases, especially cancer.
The aim of the experimental work presented in this thesis was to describe methylation patterns and their effect on gene expression in different tissue types, both healthy and cancerous. Studies of healthy human tissues confirmed a clear correlation between DNA methylation in promoter regions and gene expression.The DNA methylation patterns also clearly reflected tissue-specific functions as demonstrated with hierarchical clustering and GO analyses of hypomethylated tissue-specific differentially methylated regions(tDMRs). The tDMR analysis revealed that a large number of methylated regions were within gene body regions, yet we were not able to show how these tDMRs mechanistically contribute to tissue-specific functions.
Based on the observation that inter-individual variability in ADME gene expression affects drug efficacy, toxicity, and susceptibility to environmental toxins,we determined to what extent SNPs and DNA methylation canjointly explain variations in ADME gene expression in liver. As expected, the combination of SNP genotype and CpG site methylation levels data explained more of the observed expression variations than the use of SNP or methylation levels alone.
The last part of the thesis concentrated on describing DNA methylation patterns in early-stage non-small cell lung cancer (NSCLC) patients. A number of differentially methylated CpG sites were found, most of the identified genes represent novel markers for NSCLC.GOanalysis revealed that differentially methylated genes were closely related to cancer progression. Furthermore, a survival analysis identified a number of CpG sites whose methylation levels differed according topatient survival. Accordingly, the latter sites represent CpGs that could potentially serve as prognostic markers.