BioTechniques News
Maddy Chapman
Using a combination of single-cell genome mapping, spatial transcriptomics and AI, researchers have identified chromatin alterations as a component of Alzheimer’s disease pathology.
A collaboration between the University of Pittsburgh and Carnegie Mellon University (both PA, USA) has linked genome folding to gene activity and brain tissue organization in Alzheimer’s disease. The researchers applied innovative technologies, such as single-cell 3D genome mapping, spatial transcriptomics and a newly developed AI model, to demonstrate how altered genome folding may change gene activity, which has the potential to inform future therapeutics for a wide range of diseases in addition to Alzheimer’s disease.
Although previous Alzheimer’s research has illuminated changes in gene activity across cell types in the brain, the molecular mechanisms driving these changes remain poorly characterized. To remedy this, researchers set out to gain a multiscale view of the disease:
“Alzheimer’s disease cannot be understood one layer at a time,” explained co-senior author Jian Ma (Carnegie Mellon). “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.”
In 2024, Ma and his team unveiled genome architecture and gene expression by sequencing (GAGE-seq), a single-cell co-assay that can simultaneously measure 3D genome structure and gene expression within the same cell. Bringing this technique to University of Pittsburgh neurobiologist Hansruedi Mathys, a collaboration kicked off to apply the new technology to postmortem prefrontal cortex tissue donated by individuals involved in a dementia study at Rush University’s Alzheimer’s Disease Center (IL, USA).
In addition to the GAGE-seq data, the team collected spatial transcriptomic and chromatin accessibility data, which together allowed the researchers to map gene regulation, including molecular and cellular changes, to 3D genome organization, situating these changes within their broader tissue context.
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This analysis provided fundamental insights into the genomic architecture of Alzheimer’s disease: according to the study authors, “chromatin compartmentalization is globally weakened in [Alzheimer’s disease], with increased long-range interactions and [transcriptionally active and repressive] compartment mingling. These chromatin structural changes are associated with decreased transcriptional output and selective dysregulation of disease-relevant pathways.”
Taking the study one step further, they developed an AI model that could predict gene activity based on information input about DNA sequence and 3D genome features – called Hicformer. The model was trained on over 7500 genes across 13 cell types under both Alzheimer’s and non-Alzheimer’s conditions. The model serves as a platform for investigating how changes in genome structure impact gene activity, which has wider implications beyond Alzheimer’s research.
The team hopes that the strides they’ve taken in developing and applying the right technology for the complexity of the disease, in addition to the molecular changes observed in Alzheimer’s tissue, will inspire further research questions and, eventually, contribute to the development of targeted therapeutics. Of course, the first step in treating any condition is understanding it; a feat made easier with advanced technologies that provide contextual information.
This content is part of our Spotlight: Spatial investigations of complex tissues, in association with Takara Bio.
The post Redrawing the brain’s molecular blueprint: 3D genome mapping and AI reveal more about Alzheimer’s pathology appeared first on BioTechniques.
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