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Tissue-specific investigations of DNA methylation variation in human neurobiological diseases

University of British Columbia

Epigenomic variation represents an emerging focus in human health research, particularly in regards to neurobiological disease susceptibility and pathogenesis. DNA methylation (DNAm), which involves the covalent attachment of a methyl group to a cytosine primarily at CpG dinucleotides, has been widely assessed in the context of epigenome-wide association studies (EWASs), with DNAm associations identified across a broad range of disease states, environmental exposures and genetic backgrounds. However, DNAm profiling in neurobiological diseases is challenged by the fact that DNAm variation is highly tissue-specific and target brain tissues may be difficult or impossible to collect from postmortem samples, in living individuals undergoing treatment interventions or in pediatric populations. As such, the use of cell-culture models or accessible peripheral tissues such as blood or buccal swabs represent alternative approaches used in human neurobiological DNAm studies to identify potential biomarkers of disease or treatment response. The overarching aim of my dissertation was to apply and evaluate various tissue-specific approaches to investigate DNAm variation across different neurobiological diseases. To this end, I performed four separate studies to assess disease-associated DNAm from a) post-mortem brain samples, b) primary brain-derived cell culture models and c) accessible peripheral tissues. Specifically, I examined DNAm patterns related to Huntington’s disease pathogenesis and tissue-specific Huntingtin gene expression in postmortem human cortex samples. I subsequently compared DNAm profiles from glioblastoma multiforme tumours and matched primary cell cultures enriched for brain-tumour initiating cell populations, identifying a homeobox-enriched signature of differential DNAm between the paired samples. Beyond brain-specific DNAm patterns, I also explored the use of a disease-relevant blood cell type, CD³⁺ T-lymphocytes, to detect DNAm alterations associated with alcohol dependence in patients undergoing a clinical intervention. Finally, I assessed DNAm variability and the influence of genetic variation on DNAm in peripheral blood and buccal epithelial cells from two pediatric cohorts, highlighting a number of potential considerations and practical implications for the appropriate design and interpretation of early-life EWAS analyses in these tissues. Overall, these findings provide evidence to implicate DNAm variation in neurological function and pathology as well as present potential opportunities for the identification of novel biomarkers in accessible tissues.

Text

2019-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/67738

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/