Researchers link genome folding to gene activity and brain tissue organization in Alzheimer's

Researchers from Carnegie Mellon University's School of Computer Science, the University of Pittsburgh School of Medicine and the University of Washington shed new light on Alzheimer's disease that could point to new directions for treatment.

In a paper published in Science, researchers from SCS's Ray and Stephanie Lane Computational Biology Department, Pitt's Department of Neurobiology and collaborating institutions shows that the 3D genome architecture is organized differently in certain brain cells from people with Alzheimer's disease, uncovering a previously underexplored layer of this disease's biology. The research team linked genome folding to gene activity and brain tissue organization in Alzheimer's disease. The research team did this with single-cell technology, spatial mapping of brain tissue, and a new 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."

To build this multi-scale view, researchers analyzed postmortem tissue from the prefrontal cortex, a region at the front of the brain, obtained from individuals with and without Alzheimer's disease who had participated in a long-term study on dementia and donated their brains to science after death. The team used GAGE-seq, which measures gene expression and 3D genome contacts in the same cell. They also integrated these measurements with spatial transcriptomic maps of intact tissue. Together, these complementary data allowed the researchers to relate 3D genome organization to gene regulation and place disease-associated molecular and cellular changes within their broader tissue context.