STUDY OF EPIGENETIC SIGNATURES ASSOCIATED WITH NEURONAL DIFFERENTIATION, AGING AND ALZHEIMER’S DISEASE

Abstract

Aging is the major risk factor for Alzheimer’s disease (AD) and can be regulated by different epigenetic mechanisms, including DNA methylation and alternate splicing. My thesis focused on studying how intron retention (IR) caused by alternate splicing may change in aging and AD tissues; as well as how DNA methylation is regulated in neurogenesis. By analysing Drosophila, mouse, human and AD cohort transcriptomes, I observed increased IR in older and AD brain tissues. Moreover, many IR genes showed significant changes in their protein expression in AD tissues. This indicates that increased IR is a conserved transcriptional signature associated with aging and may be linked to AD. I also compared the performance of different computational tools that define IR. Finally, by analysing the methylome and transcriptome of specific embryonic cells lines, I found that phosphorylation of Tet3 is necessary to regulate DNA hydroxymethylation and expression of genes involved in neurogenesis.