Researchers at Carnegie Mellon University's School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington have uncovered a previously underexplored feature of Alzheimer's disease that may help scientists identify new avenues for treatment. The study, published in Science, found that the three-dimensional organization of the genome differs in certain brain cells from people with Alzheimer's disease. Scientists from SCS's Ray and Stephanie Lane Computational Biology Department, Pitt's Department of Neurobiology, and collaborating institutions connected these changes in genome folding with shifts in gene activity and the organization of brain tissue.
To build this detailed picture, the team combined single-cell technology, spatial mapping of brain tissue, and a newly developed deep learning model. "Alzheimer's disease cannot be understood one layer at a time," said Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology who led and supervised the study. "The genome's 3D structure is a fundamental regulatory layer that helps to connect DNA sequence to gene activity.
By integrating genome folding, cell state, and tissue context, we can move beyond cataloging disease-associated changes toward understanding how they fit together and which mechanisms to test next." DNA does not sit inside a cell as a simple straight strand. Instead, it folds into a complex three-dimensional structure that helps determine which genes are accessible and active. Changes in that physical organization can therefore influence how cells function.
The researchers examined postmortem samples from the prefrontal cortex, an area at the front of the brain. The tissue came from people with and without Alzheimer's disease who had taken part in a long-term dementia study and later donated their brains for research. The team used GAGE-seq, a technique that can measure both gene expression and three-dimensional genome contacts within the same individual cell.
Those measurements were then combined with spatial transcriptomic maps, which preserve information about where gene activity occurs within intact brain tissue. By bringing these datasets together, the researchers were able to connect the physical organization of the genome with gene regulation while also seeing where Alzheimer's related molecular and cellular changes appeared within the surrounding tissue. "Our study represents a major advance in understanding what goes wrong in Alzheimer's disease," said Hansruedi Mathys, assistant professor of neurobiology at Pitt's Department of Neurobiology, who directed the Pitt arm of the study.
"We know the classic hallmarks of Alzheimer's disease - accumulation of amyloid-beta plaques and tau tangles - but our results establish higher-order chromatin alterations as a component of the molecular pathology associated with the disease, which currently affects seven million Americans, a number that continues to grow." Amyloid beta plaques and tau tangles are among the best known biological features of Alzheimer's disease. The new findings suggest that changes in chromatin, the material made of DNA and associated proteins that packages the genome inside cells, should also be considered part of the disease's molecular landscape. AI Connects Genome Folding to Gene Activity Another important part of the research was Hicformer, an artificial intelligence model developed to investigate how genome structure may influence cellular behavior.
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