Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/6043
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dc.contributor.authorBurgers, Marjolein Johanna-
dc.date.accessioned2024-02-02T11:05:22Z-
dc.date.available2024-02-02T11:05:22Z-
dc.date.issued2023-
dc.identifier.urihttp://hdl.handle.net/10443/6043-
dc.descriptionPhD Thesisen_US
dc.description.abstractOsteoarthritis (OA) is a degenerative joint disease and a leading cause of global disability in people over the age of 50. A genome-wide DNA methylation meta-analysis performed in our laboratory identified OA-associated DNA methylation changes in hip and knee cartilage, which were depleted in gene promoters and highly enriched in putative enhancer regions. Enhancers are short regulatory elements that regulate gene expression spatiotemporally. DNA methylation changes at enhancer regions can be involved in gene expression regulation, and therefore this project aimed to study the effect of OA-associated DNA methylation changes within enhancer region on gene expression regulation. First, OA-associated DNA methylation changes in 21 putative chondrogenic enhancer regions were selected and validated by bisulphite pyrosequencing in hip cartilage samples. Analysis of 31 tissues from the Roadmap Epigenomics project revealed enhancer chromatin state associated CpG sites in eight of these enhancer regions, DNA methylation levels at these CpG sites were reduced in tissues with an enhancer chromatin state at this region. Then, in order to gain more insight in the epigenetic alterations upon DNA methylation changes genome-wide, pharmacological inhibition of DNA methylation in human SW1353 chondrosarcoma cells was studied in relation to DNA methylation (Illumina EPIC array), chromatin accessibility (ATAC-seq), chromatin states (ChIP seq), and gene expression (RNA-seq). Finally, using CRISPR mediated genetic and epigenetic modifications and targeted chromatin interaction analysis, the target genes of five validated enhancer regions with OA-associated DNA methylation changes were identified, of which DNA methylation at three enhancer regions were associate with gene expression in hip cartilage. In conclusion, this work identified OA-associated DNA methylation changes located in enhancer regions and explored the effect of DNA methylation changes on gene expression regulation. Understanding how enhancer DNA methylation regulates gene expression will give more insight in OA progression and possible treatment.en_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleOsteoarthritis-associated DNA methylation changes in chondrogenic enhancer regions in relation to gene expression regulationen_US
dc.typeThesisen_US
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