Browsing by Subject "DNA Methylation"
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Item Epigenetic Regulation of Gene Expression in Alzheimer’s disease(2016-05-01) Shewale, Shantanu J.; John V. Planz; Arthur J. EisenbergAlzheimer’s disease (AD) is the most common form of age-related neurodegenerative dementia, and it is estimated that over 5 million people currently have AD within United States. AD can either be early onset or Late Onset AD (LOAD). Early onset AD has an age of onset below 60 years, and LOAD has an age of onset of above 65 years. Early onset AD accounts for 95% of AD cases, and numerous genetic loci have been linked to LOAD; these loci have small effect sizes, and explain only 50% of AD risk. We hypothesize that epigenetic mechanisms are responsible for a significant portion of this missing heritability. The impact of epigenetic mechanisms on AD risk and progression are relatively unexplored, and should be considered when addressing a portion of the remaining missing heritability. Within this project, post mortem frontal cortex brain tissue from 11 AD patients and 12 age matched controls were used to investigate DNA methylation and differential gene expression in AD. Since post mortem human tissue was used, preliminary analysis showed presence of degraded RNA, most likely due to post mortem intervals. To combat degraded RNA, a novel library preparation process was utilized prior to performing RNA sequencing. DNA methylation was investigated using two methods. For site specific investigation, the Illumina® Infinium HumanMethylation450 BeadChip array was utilized. To investigate differential methylated regions, a Methyl-Binding Protein capture approach was used to precipitate out methylated regions of the genome. This precipitated DNA was then analyzed for methylated regions by using high throughput sequencing. The Differentially Expressed Genes (DEGs) found within our RNA-seq dataset all elucidate the importance of some previously suspected pathways involved in the pathogenesis of AD. Gene Ontology (GO) analysis performed indicate that DEGs implicate numerous genes correlated with neurological disease, and collectively effect regulation of synaptic transmission, cell-cell signaling, neurotransmitter transport, genes involved in the inflammatory response, and Amyloid Precursor Protein (APP) processing. The overlap of 32 DEGs and differentially methylated CpGs was observed. GO analysis demonstrated the same GO terms (synaptic transmission & cell-cell signaling) impacted within both, RNA and DNA datasets. This indicates a link between CpG methylation and differential gene expression.Item Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy(BioMed Central Ltd., 2020-05-19) Silzer, Talisa K.; Pathak, Gita A.; Phillips, Nicole R.BACKGROUND: Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. METHODS: Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. RESULTS: Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. CONCLUSION: With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.