Science (New York, N.Y.) · 2026
Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease.
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Zhang Yang, Lu Xinyue, Kunisky Alexander K, Alam Shahul, Tang Junjie, Zhang Ruochi, Wang Shike, Zhang Han, Baroudi Jude, Ichcho Walid, Jia Deyong, Ghorbanikalateh Sahar, Ghorbanikalateh Sahel, Wang Shihan, Bennett David A, Mathys Hansruedi, Duan Zhijun, Ma Jian
Аннотация
Alzheimer's disease (AD) disrupts brain function through cell type-specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type-specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type-specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration.