Three-Dimensional Chromatin Architecture Landscape of Aging and Alzheimer's Disease

Abstract

Recently, accumulating genetic and epigenetic studies are indicating a close association between dysregulated enhancers and Alzheimer's disease (AD). However, their contributions were poorly defined for lacking direct links to disease genes. To bridge this gap, we presented the maps of three-dimensional chromatin architecture of brain tissue of AD patients, dementia-free aged and young individuals. We found that AD patients were more affected by the dynamic of 3D -chromatin architecture. There were four classes of long-distance interaction changes. Among them, the feedback class was more observed, indicating the prevalence of feedback loops during AD genesis. Integrating with epigenetic data, a new strategy was proposed to improve the resolution of Hi-C data. Hence, we observed more detailed interactions among active genomic regions and found that known AD risk genes were under long-distance promoter-enhancer interactions. As an application, we utilized the Hi-C loops to link the AD risk SNPs to target genes and to identify the dysregulated genes. Functional annotation suggested that long-distance interaction changes contributed to AD genesis by disrupting brain function-related pathways. For future AD and aging studies, our result provides a reference landscape to better interpret signals of association and epigenetic studies.