2024/09/08 by Zechuan Shi, Sudeshna Das, Samuel Morabito +12 · 1 voice
Medicine · Neuroscience · Biochemistry, Genetics and Molecular Biology · #Alzheimer's disease research and treatments #Neuroinflammation and Neurodegeneration Mechanisms #Bioinformatics and Genomic Networks
paper · doi:10.1101/2024.09.06.611761
openalex publication_date 2024/09/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
The study of neurodegenerative diseases, particularly tauopathies like Pick's disease (PiD) and Alzheimer's disease (AD), offers insights into the underlying regulatory mechanisms. By investigating epigenomic variations in these conditions, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database (http://swaruplab.bio.uci.edu/scROAD) to visualize predicted single-cell TF occupancy and regulatory networks.