DNA Hypermethylation of Promoter CpG Islands in Cancer
2017
Hochschulschrift
Zugriff:
DNA cytosine methylation is an important epigenetic modification that plays a key role in demarcation of regulatory regions involved in controlling gene expression. In normal cells the bulk of the genome is methylated, whereas key regulatory regions, such as promoter CpG islands, are maintained in an unmethylated state. In cancer, while the majority of CpG islands remain unmethylated, a number of CpG islands undergo aberrant DNA hypermethylation. A widely studied, but still unresolved question to date is to understand what triggers the aberrant changes to the promoter CpG island methylation landscape in cancer. The recent discovery of DNA hydroxymethylation as a critical facilitator of DNA demethylation together with its widespread depletion in carcinogenesis has provided a new layer to this question suggesting a specific role for DNA hydroxymethylation in the aberrant changes to the DNA methylation landscape. In this study I analysed whole-genome bisulphite sequencing (WGBS), performed TET-assisted bisulphite sequencing (TAB-seq) and exploited several chromatin modification profiles (ChIP-seq) to elucidate the role of DNA hydroxymethylation and chromatin modifications in aberrant DNA methylation of promoter CpG islands in prostate cancer. In addition to the well-described hypermethylation of the entire CpG island, I observed a novel mode of aberrant methylation that entails an encroachment of methylation across 5’ and/or 3’ CpG island borders, resulting in smaller islands and new discreet CpG island borders. Importantly, I found that DNA hydroxymethylation showed distinct enrichment patterns across the different groups of promoter CpG islands, in concordance with their predisposition to hypermethylation in cancer. Integrative analysis of WGBS and ChiP-seq data revealed that in normal prostate epithelial cells, nucleosomes carrying H3K4me1 modification pre-mark borders of promoter CpG islands prone to aberrant hypermethylation in cancer, including the novel mode of DNA methylation encroachment. Significantly, I showed that depletion of histone H3K4me1 in the mouse model harboring a loss-of-function mutation of the gene encoding H3K4 methyltransferase KMT2D, resulted in a reduction of DNA methylation at the borders of promoters and expansion of the unmethylated regulatory regions. Overall, my work shows for the first time that there is a critical relationship between the organization of DNA hydroxymethylation, H3K4me1-marked nucleosomes and demarcation of DNA methylation borders at CpG island gene promoters in normal cells and their predisposition to DNA hypermethylation in cancer.
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DNA Hypermethylation of Promoter CpG Islands in Cancer
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Autor/in / Beteiligte Person: | Skvortsova, Ksenia |
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Veröffentlichung: | 2017 |
Medientyp: | Hochschulschrift |
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