Researchers at Carnegie Mellon University, the University of Pittsburgh, and the University of Washington have discovered that the three-dimensional organization of the genome differs in certain brain cells from people with Alzheimer’s disease, according to a study published in Science. According to Jian Ma, who led and supervised the study at Carnegie Mellon’s School of Computer Science, the findings connect changes in genome folding with shifts in gene activity and brain tissue organization to help scientists identify new avenues for treatment.
Beyond Amyloid and Tau: How 3D Genome Folding Impacts Alzheimer’s
According to Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology who led the research, Alzheimer’s disease cannot be understood one layer at a time. DNA inside a cell does not sit as a straight strand; instead, it folds into a complex three-dimensional structure that helps determine gene accessibility and activity. According to the study, researchers examined postmortem samples from the prefrontal cortex taken from people with and without Alzheimer’s disease.
For the purpose of constructing this comprehensive view, the group integrated spatial brain tissue mapping, single-cell technology, and a novel deep learning algorithm known as Hicformer. Hansruedi Mathys, an assistant professor of neurobiology at the University of Pittsburgh Department of Neurobiology, noted that the findings demonstrate higher-order chromatin shifts as part of the molecular pathology linked to the condition, which currently impacts seven million Americans.
Did you know?
According to the research team, GAGE-seq is a specialized technique that measures both gene expression and three-dimensional genome contacts within the same individual cell, allowing scientists to directly link chromosome structure with disease-related gene programs.
AI Models Connect Chromosome Structure to Gene Activity
To investigate how genome structure influences cellular behavior, the research team developed an artificial intelligence model named Hicformer. According to Xinyue Lu, a doctoral student in Computational Biology who co-led the research, the system functions as a computational test bed to explore how changes in genome folding alter gene activity. Yang Zhang, a project scientist in the Computational Biology Department, stated that this paired view revealed a consistent signature of 3D genome reorganization across several kinds of brain cells.
DNA Organization and Compartment Mingling in Affected Cells
The research identified consistent differences in the genome architecture of cells from people with Alzheimer’s disease. Large sections of the genome normally organized into distinct active and inactive regions, known as compartments, appeared less sharply defined in Alzheimer’s cells. According to the study’s findings, the team described this pattern as increased compartment mingling, which correlated with lower overall levels of gene activity.
According to the findings, several kinds of brain cells showed fewer interactions between nearby sections of the genome and more contacts between regions located farther apart. These structural differences were linked to reduced activity in programs involved in neurons and synapses, metabolism, and cellular stress responses, alongside connections to senescence-related programs in microglia.
Frequently Asked Questions
What is GAGE-seq?
According to the study, GAGE-seq is a technique that measures both gene expression and three-dimensional genome contacts within the same individual cell.
What role does Hicformer play in the research?
According to Xinyue Lu and Yang Zhang, Hicformer is an artificial intelligence model that combines DNA sequence information with broad patterns of genome folding to predict gene activity across different cell types.
Which institutions collaborated on this Alzheimer’s study?
According to the published research, investigators from Carnegie Mellon University’s School of Computer Science, the University of Pittsburgh School of Medicine, and the University of Washington collaborated on the project alongside researchers from the Broad Institute of MIT and Harvard, the University of California, Los Angeles, and the Rush Alzheimer’s Disease Center.
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