THESIS
2018
ix, 70 pages : illustrations (some color) ; 30 cm
Abstract
Aberrant DNA methylation is commonly observed in cancer genomes, including focal
gene promoter hypermethylation and global hypomethylation. While the gain of this repressive
epigenetic modification at gene promoter has been relatively well studied, global loss of DNA
methylation in cancer cells remains poorly understood. As previously reported, the loss of DNA
methylation results in the formation of partially methylated domains (PMDs), large genomic
segments with reduced DNA methylation. Intriguingly, genes residing in PMDs show little to
no transcriptional change, potentially compensated by the histone H3 lysine 9 tri-methylation
(H3K9me3) and histone H3 lysine 27 tri-methylation (H3K27me3) repressive histone
modifications. We have observed that large PMDs are typically enriche...[
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Aberrant DNA methylation is commonly observed in cancer genomes, including focal
gene promoter hypermethylation and global hypomethylation. While the gain of this repressive
epigenetic modification at gene promoter has been relatively well studied, global loss of DNA
methylation in cancer cells remains poorly understood. As previously reported, the loss of DNA
methylation results in the formation of partially methylated domains (PMDs), large genomic
segments with reduced DNA methylation. Intriguingly, genes residing in PMDs show little to
no transcriptional change, potentially compensated by the histone H3 lysine 9 tri-methylation
(H3K9me3) and histone H3 lysine 27 tri-methylation (H3K27me3) repressive histone
modifications. We have observed that large PMDs are typically enriched with both of these
repressive epigenetic marks in a particular pattern. Therefore, we hypothesize that occupancy
of H3K27me3 at the boundaries might act as a barrier in demarcating PMDs. Using A375, a
melanoma cell line, as a model, we employed techniques to analyze the epigenome including
whole genome bisulfite sequencing (MethylC-seq) and chromatin immunoprecipitation
sequencing (ChIP-seq). Furthermore, we utilized several approaches to engineer either the
genomic sequence or epigenomic marks at PMDs boundaries and studied their effects on other
epigenetic marks. This study aims to elucidate the interplay between distinct epigenetic
modifications.
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