Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer’s disease
Abstract
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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (18)
Yang Zhang
Xinyue Lu
Alexander K. Kunisky
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Shahul Alam
Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
Junjie Tang
Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
Ruochi Zhang
Shike Wang
Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
Han Zhang
Jude Baroudi
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Walid Ichcho
Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.
Deyong Jia
Department of Urology, University of Washington, Seattle, WA, USA.
Sahar Ghorbanikalateh
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Sahel Ghorbanikalateh
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Shihan Wang
Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
David A. Bennett
Hansruedi Mathys
Zhijun Duan
Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.
Jian Ma