Alzheimer’s disease (AD) is the most common cause of dementia, and while advances have been made in understanding its pathology, the genomic and epigenomic mechanisms remain poorly resolved, particularly through multi-omic analyses of patient cohorts. In exploring the relationship between transcriptomic and epigenomic regulation, this study investigates the changing in the binding sites of CCCTC-binding factor (CTCF) across the clinical stages of Alzheimer’s disease (AD). Using dorsolateral prefrontal cortex samples (Brodmann area 46) from the Rush Alzheimer’s Disease cohort (ENCODE Project Consortium, 2012, Luo et al., 2020), CTCF chromatin immunoprecipitation sequencing (ChIP-seq) data were integrated with RNA sequencing (RNA-seq) (Figure 1). Differential binding analysis was conducted with DiffBind and edgeR (R Core Team, 2024), and peak annotation performed with ChIPseeker. Comparisons of CTCF binding across Alzheimer’s disease stages revealed that the reduction in CTCF occupancy is not global but region-specific. Principal component analysis distinguished between early- and late-stage AD, and differential binding identified over a thousand significantly altered sites, many of which were located in promoters and intronic regions. Integration with RNA-seq uncovered hundreds of differentially expressed genes enriched in synaptic organization and cell adhesion pathways. Case examples of neuronal genes demonstrated that CTCF redistribution influences transcription in a location-dependent manner, underscoring its role in AD-related regulatory alterations. In contrast to previous binary comparisons of controls versus Alzheimer's disease (Patel et al., 2023), this multistage approach reveals progressive, site-specific, and adaptive remodeling of CTCF binding. Jointly, the findings suggest that Alzheimer's disease progression does not involve a global breakdown of chromatin insulation, but rather dynamic, environment-dependent regulatory adaptations, linking three-dimensional genome remodeling to synaptic and transcriptional dysfunction (Moral-Morales et al., 2023, Xiong et al., 2023, Zheng & Wang, 2024).
Λίλη Ν. Χρυστάλλα (Wed,) studied this question.