Title

Epigenetic Regulation of Gene Expression in Alzheimer’s disease

Date of Award

5-1-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

John V. Planz

Second Advisor

Arthur J. Eisenberg

Abstract

Alzheimer’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.

Comments

Shewale, Shantanu J., Epigenetic Regulation of Gene Expression in Alzheimer’s disease. Doctor of Philosophy (Biomedical Sciences, Molecular and Medical Genetics), April 2016, 162pp., 13 tables, 21 illustrations, bibliography, 225 titles. Available May 2018.

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