Scientists identify changes in 3D genome organization in Alzheimer’s disease
Researchers from Carnegie Mellon University, the University of Pittsburgh School of Medicine, Washington University and other institutions have found that the three-dimensional organization of the genome changes in certain brain cells of people with Alzheimer’s disease. These changes are associated with shifts in gene activity and the spatial organization of brain tissue, ScienceDaily reports.
The study results were published in the journal Science. The scientists analyzed postmortem samples of the prefrontal cortex from people with and without Alzheimer’s disease. The participants were involved in a long-term dementia study and donated their brains for scientific research after death.
How DNA changes were studied
DNA in a cell does not exist as a straight strand but folds into a complex three-dimensional structure. This organization affects which genes are accessible and active and can therefore influence how cells function.
The team used GAGE-seq technology, which makes it possible to measure gene expression and three-dimensional genome contacts within a single cell. These data were combined with spatial transcriptomic maps that retain information about where genes are active in intact brain tissue.
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The researchers also used the Hicformer deep-learning model. It combines information about DNA sequence, general patterns of genome folding and maps of physical contacts between its regions to predict gene activity in different cell types.
Less distinct boundaries of genomic regions
In cells from people with Alzheimer’s disease, large active and inactive regions of the genome, known as compartments, had less distinct boundaries. The authors called this phenomenon increased compartment mixing. In several types of brain cells, they also recorded fewer contacts between nearby genome regions and more contacts between distant regions.
Cells with more pronounced compartment mixing generally had lower levels of gene activity. The researchers also identified weaker interactions between genes and nearby regulatory elements that control whether they are switched on or off, while some contacts at intermediate distances became stronger.
These structural differences were linked to reduced activity of gene programs associated with neurons and synapses, as well as changes in metabolism and cellular stress responses. The researchers also found an association with cellular aging programs in microglia, the brain’s immune cells. Further studies may test whether specific changes in genome architecture contribute to the development of the disease and whether affected regulatory regions could later become targets for therapeutic research.
