A multi-institutional study finds consistent alterations in chromatin architecture and gene regulation across several brain cell types in Alzheimer’s, using single-cell genome-contact mapping, spatial maps of brain tissue, and a new computational model.
The team measured genome contacts and gene expression in the same single cells (GAGE-seq) and mapped those measurements onto intact brain tissue using spatial transcriptomics.
Hicformer, a newly developed computational model, links genome folding and DNA sequence to predict gene activity and prioritize regulatory regions for follow-up.
Chromatin reorganization is presented as an additional molecular component of Alzheimer’s alongside amyloid and tau, suggesting new targets for mechanistic study and therapeutic exploration.
# What the study found Researchers working at Carnegie Mellon University, the University of Pittsburgh, and the University of Washington report that the three-dimensional arrangement of DNA inside brain cells differs between people with and without Alzheimer's disease. Those differences in genome folding correlate with changes in which genes are switched on and off in affected cells.
# Why this matters DNA is not a straight string inside the nucleus. It folds into loops and compartments that bring regulatory regions and genes into physical contact. Those contacts influence gene activity. The study argues that changes in higher-order chromatin structure belong to the molecular picture of Alzheimer's disease, alongside amyloid-beta plaques and tau tangles.
# How the team studied genome structure and activity The researchers combined three types of data:
# Main biological observations Across several kinds of brain cells, the team identified a reproducible signature of 3D genome reorganization associated with Alzheimer's. The study reports that chromatin — the combination of DNA and its associated proteins that packages the genome — becomes less distinctly organized in disease-affected cells, and those structural changes accompany shifts in gene expression.
Hansruedi Mathys of the University of Pittsburgh described these higher-order chromatin alterations as part of the disease's molecular landscape. Jian Ma of Carnegie Mellon framed the genome's 3D structure as a regulatory layer that helps bridge DNA sequence and gene activity, and as a necessary layer to study if researchers want to move beyond cataloging changes toward testing mechanisms.
# Role of Hicformer Hicformer is a computational system developed by the team to explore how genome folding might influence cellular behavior. It combines DNA sequence with broad and fine-scale maps of genome contacts to predict which genes will be active in particular cell types or states. The model served as a "test bed" to prioritize regulatory regions that may mediate the observed gene-expression changes linked to altered folding.
# What this means for Alzheimer's research and next steps
# Which institutions and publication The work was led by teams in Carnegie Mellon's Ray and Stephanie Lane Computational Biology Department, Pitt's Department of Neurobiology, and collaborators at the University of Washington. The study was published in Science.
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