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Boden, Kirsty (2019) Investigation into patterns of epigenetic regulation of Alzheimer’s disease. PhD thesis, University of Nottingham.

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Abstract

Aberrant global and gene specific DNA methylation has been identified in late onset Alzheimer’s disease (LOAD) and has also been linked to its pathology. In addition, multiple loci associated with LOAD via genome wide association studies (GWAS) studies are being shown to harbour Alzheimer’s disease (AD) associated differential methylation in the LOAD brain. One aim of this thesis was to investigate if any differential methylation could be identified within the promoter regions of LOAD associated loci using leukocyte DNA, both for regions already identified as being aberrantly methylated in AD and those that have not been. This included the promoter regions of the genes INPP5D, SIRT1, HLA-DRB1/5, SORL1 and PTK2B. Of these genes only promoter methylation of INPP5D and SORL1 were identified in LOAD blood samples.

Work was also conducted to investigate the promoter methylation status of the genes SIRT1, TREM2, ABCA7, MEF2C and PTK2β in sporadic early onset AD samples (sEOAD). The aim being to identify if any LOAD associated differential methylation also occurs in this other sub-group of AD. No differential methylation was identified at the promoter regions of any of these genes in either sEOAD blood (leukocyte) or brain (cortex) tissue. However, significant hypomethylation of a CpG site located upstream of the MEF2C promoter was identified in the blood of one sEOAD patient, potentially representing the presence of an AD associated epi-allele. Interestingly a region containing seven CpG sites, located within the RIN3 3’UTR, was also found to be hypomethylated in sEOAD leukocyte samples. Both results indicated the importance of non-promoter CpG site methylation in AD.

A whole genome bisulphite sequencing (WGBS) study was also conducted to identify differential methylation occurring within LOAD at differing sages of disease progression. For this cerebellum DNA was used from a moderate (braak stage IV) and severe (braak stage VI) patient and data was compared to published control data. This experiment identified a significant amount of differentially methylated loci in the severe LOAD suffer when compared to the moderate patient sample and twenty two genes were identified as being associated with this aberrant methylation.

Interestingly the majority of differentially methylated cytosines were located within non-CpG dincleotides, suggesting a potential role for non-CpG site methylation in LOAD. In addition, most differential methylation identified was either downstream of the promoter or intragenically located, again suggesting an important role for non-promoter methylation in AD.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Bottley, Andrew Seymour, Graham Morgan, Kevin
Keywords:	Alzheimer’s disease, epigenetic regulation, Genetic regulation, Epigenesis
Subjects:	Q Science > QH Natural history. Biology > QH426 Genetics
Faculties/Schools:	UK Campuses > Faculty of Science > School of Biosciences
Item ID:	58945
Depositing User:	Boden, Kirsty
Date Deposited:	04 Oct 2023 07:35
Last Modified:	04 Oct 2023 07:35
URI:	https://eprints.nottingham.ac.uk/id/eprint/58945

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