Taiwo, OO; (2013) The role of DNA methylation in stem cell ageing. Doctoral thesis , UCL (University College London).

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Abstract

Ageing is a major factor contributing to human morbidity and disease, including cancer. To study the possible involvement of epigenetic changes in ageing, murine haematopoiesis was used as a model system. The key cells determining ageing in this system are thought to be lower side population (LSP) cells of the bone marrow, which are enriched for long-term reconstituting haematopoietic stem cells (LT-HSCs). In this thesis, rare primary LT-HSCs from young, middle-aged and old mice were isolated and phenotyped. A protocol, termed Nano-MeDIP-seq was developed for methylome analyses on such rare cells. DNA and RNA from these cells were then subjected to comprehensive methylome (MeDIP-seq) and transcriptome (RNA-seq) analysis. Age-related changes in the LT-HSC methylome and transcriptome were observed in this study, many at genes associated with migration/adhesion and not previously implicated in ageing. These changes also include directional (young to old) global loss of DNA methylation of approximately 5%, 111 significantly (FDR < 0.2) age differentially methylated regions (aDMR) and more than one thousand significantly (FDR < 0.05) differentially expressed transcripts. Ingenuity pathway analysis (IPA) identified significant (p << 0.0001) age-related decline in B-Cell development and significant (p << 0.0001) alterations in pathways and functions associated with cell movement. A number of genes were identified to be significantly age differentially methylated and differentially expressed. One aDMR, associated with the Serum deprivation protein response (Sdpr) gene, was functionally validated to demonstrate a negative correlation between promoter methylation and differential expression. The findings in this thesis support a model involving an epigenetic dysregulation of the genes that control the interaction between LT-HSCs and their regulatory niche, during physiological ageing.

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