Photo caption: Hansruedi Mathys, assistant professor of neurobiology, School of Medicine, University of Pittsburgh. Photography by Joshua Franzos.
Researchers from Pitt and Carnegie Mellon University used single-cell 3D genome mapping, spatial transcriptomics and an AI model to uncover “compartment mingling” in Alzheimer’s brain cells. The finding links altered chromatin organization to gene activity, brain tissue changes and Alzheimer’s disease pathology.
By Allison Hydzik, UPMC Media Relations, and Marylee Williams, Carnegie Mellon University
When Carnegie Mellon University computer scientist Jian Ma approached Hansruedi Mathys, assistant professor of neurobiology at the University of Pittsburgh, about applying his team’s new single-cell 3D genome mapping technique to brain cells donated by people with Alzheimer’s disease, Mathys didn’t even have to consider his answer.
“Of course, I didn’t hesitate—when he proposed we do this study together, I was very excited,” Mathys said. “It was an opportunity to help ensure that people who passed away with Alzheimer’s and had chosen to donate their brains to research could contribute to solving the mystery of this disease and, hopefully, preventing it in the future.”
In a paper published in Science, the research team showed that—when mapped in 3D—the genome architecture is organized differently in certain brain cells donated by people with Alzheimer’s disease compared to those without, uncovering a previously underexplored layer of this disease’s biology. With single-cell technology, spatial mapping of brain tissue and a new deep learning model, the team linked genome folding to gene activity and brain tissue organization in Alzheimer’s disease.
“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,” said Mathys, cosenior author of the Science paper.
How is genetic information different in Alzheimer’s brain cells?
Chromatin is a complex of DNA and proteins that organizes long DNA strands so they fit in a cell’s nucleus in compartments.
Using Ma’s breakthrough technology—which he developed with Zhijun Duan, research associate professor in the University of Washington Division of Hematology and Oncology—the team discovered that large active and inactive regions of the genome, known as compartments, were less clearly separated in brain cells from people with Alzheimer's. It’s a pattern the team calls “increased compartment mingling.”
Multiple kinds of brain cells showed fewer short-range contacts and more long-range contacts, and greater compartment mingling was associated with lower overall gene activity. Contacts between genes and nearby regulatory elements that help control gene activity also weakened, while some midrange contacts strengthened. These architectural alterations were linked to reduced neuronal and synaptic programs, altered metabolic and stress responses, and stabilization in brain immune cells called microglia.
“Alzheimer’s disease cannot be understood one layer at a time,” said cosenior author Jian Ma, the Ray and Stephanie Lane Professor of Computational Biology at Carnegie Mellon 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 multiscale 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 at Rush University’s Alzheimer’s Disease Center 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.
Another major advance was the development Hicformer, an AI model that combines DNA sequence, broad genome-folding features and local 3D contact maps to predict gene activity in different kinds of cells. The scientists describe it as a computational “test bed” for asking how altered genome folding may change gene activity.
How can this discovery lead to therapies for Alzheimer’s disease?
The technology could be applied to numerous diseases, but the team chose Alzheimer’s, in part, because of its growing prevalence, said Mathys.
“Just a few years ago, when I would give talks about Alzheimer’s, I’d have a slide that said it affected five million people—now it’s seven million,” he said. “It’s increasing so rapidly and the majority of cases are sporadic, or late onset, for which the cause of the disease is not really known.”
The new, fundamental discovery about the genome architecture within the brain cells of people with Alzheimer’s disease gives rise to numerous questions that could each spark research pathways, Mathys said. These include determining whether the differences in genome structure cause the disease pathology or if the pathology is causing the changes, why some people have the differences while others don’t, and if people who have signs of Alzheimer’s pathology but no clinical symptoms have the genome organization differences. And, ultimately, if answering these questions could reveal new therapeutic targets.
“If we don’t know what is happening in Alzheimer’s disease, we can’t think of ways to prevent it,” Mathys said. “So, if we’re ever going to stop Alzheimer’s, understanding it must be a top priority.”
Additional authors and funding sources
Additional Pitt authors on this research are doctoral students Alexander K. Kunisky and Jude Baroudi, postbaccalaureate research fellows Sahar and Sahel Ghorbanikalateh and visiting scholar Shihan Wang. Other Carnegie Mellon authors are doctoral students Xinyue Lu, Shahul Alam and Shike Wang, project scientist Yang Zhang and postdoctoral research associate Junjie Tang. The team included researchers from the Broad Institute of MIT and Harvard, the University of California, Los Angeles, the University of Washington and the Rush Alzheimer’s Disease Center.
This research was supported by National Institutes of Health (NIH) grants R01HG012303, R56HG013092, R01HG007352, R21DA061481, R61DA047010, P30AG10161, P30AG72975, R01AG17917, R01AG015819, U01AG072572 and U01AG046152; NIH Common Fund 4DN Program grants UM1HG011593 and UM1HG011586; NIH Common Fund SenNet Program grant UH3CA268202.
Media Contact: HSNEWS@pitt.edu