Yaman, Umran; (2025) Genome-wide long-read transcriptomics and DNA methylation in App NL-G-F knock-in mouse model of Alzheimer’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder driven by genetic and epigenetic changes. Genome-wide association studies (GWAS) have identified a network of AD risk genes, primarily expressed in microglia. However, short-read sequencing often fails to capture transcript diversity, isoform-level alterations, and alternative splicing, limiting understanding of how genetic risk variants regulate gene expression and contribute to disease progression. This thesis describes and presents the use of long-read RNA and DNA sequencing, which was performed as a part of this study, in the AppNL-G-F knock-in mouse model to address these limitations. By integrating transcriptional and epigenetic analyses, differential alternative splicing, novel transcript isoforms, and genome-wide DNA methylation patterns were investigated to uncover mechanisms underlying AD. Long-read RNA sequencing identified activation of microglial AD risk genes, such as Trem2, and novel isoforms in AD-associated genes. Isoform usage and alternative splicing were also observed in genes not previously linked to AD, including Syngr1 and Clta, which influence synaptic function. These findings highlight the importance of profiling splicing and isoform alterations across diverse brain cell types, including microglia, neurons, and oligodendrocytes. Genome-wide DNA methylation analysis revealed differentially methylated regions (DMRs) in AD-related genes such as App and Mapt. Many human AD risk genes and differentially spliced genes overlapped with DMRs. Strong correlations between methylation and gene expression were observed in Capg and Csf1, emphasizing the role of methylation in fine-tuning expression. Hypermethylated promoters were linked to RNA splicing and stem cell maintenance, while hypomethylated promoters were associated with immune activation and cell trafficking. DMRs extending into gene bodies and intergenic regions were enriched in inhibitory neurons, suggesting connections between synaptic regulation and microglial interactions during amyloid response. This thesis demonstrates the utility of long-read sequencing in revealing AD mechanisms, providing insights into amyloid pathology and potential therapeutic targets.

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