Active and less active DNA regions are less clearly separated in brain cells in Alzheimer’s disease
Active and less active DNA regions are less clearly separated in brain cells in Alzheimer’s disease
In a Science article published on July 23, teams from Carnegie Mellon, the University of Pittsburgh, and the University of Washington measured gene activity and three-dimensional DNA contacts in the same brain cells. The Hicformer model showed that these contacts help predict disease-associated changes in gene activity.
DNA in the nucleus is not simply a long strand. Regions containing frequently transcribed genes usually lie near other active regions, while less active regions cluster separately. Which DNA fragments come into contact helps determine whether a regulatory region can affect a gene’s activity.
The authors applied GAGE-seq to individual cells from the postmortem prefrontal cortex of people with Alzheimer’s disease and people without the diagnosis. The method simultaneously measures gene activity and contacts between distant regions of chromatin, the material that makes up chromosomes. A spatial map of the tissue then showed where cells with different patterns of gene activity and DNA organization were located in the cortex.
In people with Alzheimer’s disease, large active and less active regions of the genome were less clearly separated. The authors describe this as compartment mixing. In several cell types, they also found fewer short-range DNA contacts and more long-range contacts. Connections between genes and nearby regulatory regions were weaker. At the same time, the activity of synapse-related genes decreased in neurons, while programs related to stress, metabolism, and cellular aging changed in microglia, the immune cells of the brain.
Hicformer compares the DNA sequence, its overall organization, and local contacts to predict gene activity across different cell types. According to the authors, the model was less effective at identifying disease-associated changes in gene activity when information about three-dimensional contacts was excluded. This means that a map of DNA contacts adds another way to identify cells and regulatory regions for further experiments beyond simply listing which genes are active or inactive.
Amyloid plaques and tau tangles remain prominent features of the disease. This study describes another part of the picture: cells differ not only in which genes are active, but also in the positions of the DNA regions that may regulate those genes.