Human brains contain a complex network of cells that communicate and interact in intricate ways. As brain cells grow and age, interactions between genetic components like chromatin and RNA change, impacting crucial cellular function. Now, new research from scientists at the University of California (UC), San Diego, is elucidating the nuances of those interactions. 

Their findings indicate that some brain cells that age more rapidly than others are disproportionately abundant in individuals that have Alzheimer’s disease. They also found sex-specific differences in the aging processes of cells. Specifically, when they compared brain cells in mice, the female cortex had a much higher ratio of old oligodendrocytes to old neurons compared to the male cortex. Full details are provided in a Nature paper titled, “Single-cell multiplex chromatin and RNA interactions in aging human brain.”

The discoveries were made possible by a technique designed by the UC San Diego team that is called Multinucleic Acid Interaction Mapping in Single Cells or MUSIC, “which enables the simultaneous profiling of gene expression and co-complexed DNA sequences with or without co-complexed RNA at the single-cell level.” Its workflow contains two major steps. In the first, an RNA linker is ligated to RNA molecules while a DNA linker is ligated to fragmented DNA and cell barcodes are added. The second adds a complex barcode to RNA and DNA in the same molecular complex.

The benefit of the technique is that it lets researchers look inside individual brain cells and map out interactions between chromatin. Scientists can visualize interactions at single-cell resolution, as well as study how these interactions influence gene expression. This tool has the potential “to help us uncover novel molecular mechanisms underlying Alzheimer’s pathology, which could pave the way for more targeted therapeutic interventions and improved patient outcomes,” said Sheng Zhong, PhD, a professor in the bioengineering department at the UC San Diego Jacobs School of Engineering and senior author on the study. 

Among other studies, Zhong’s team used MUSIC to analyze postmortem brain samples from human frontal cortex tissues and elsewhere in the brain. These samples were obtained from 14 donors aged 59 years and older, some with Alzheimer’s disease and some without. The results showed that different types of brain cells exhibited distinct patterns of interactions between chromatin and RNA. Interestingly, cells with fewer short-range chromatin interactions tended to display signs of aging and Alzheimer’s disease. Notably, individuals with Alzheimer’s disease had a higher proportion of these older brain cells compared to healthy individuals.

The study also uncovered sex-specific differences in the aging of brain cells. In the cortex of female mice, researchers found a higher ratio of aged oligodendrocytes to aged neurons. Given their role in maintaining normal brain function, more aged oligodendrocytes could potentially exacerbate cognitive decline.

“If we could identify the dysregulated genes in these aged cells and understand their functions in the local chromatin structure, we could also identify new potential therapeutic targets,” said Xingzhao Wen, a bioinformatics PhD candidate in Zhong’s lab and a co-first author on the study. Furthermore, “the disproportionate presence of old oligodendrocytes in the female cortex could shed new light on the increased risks of neurodegenerative and mental disorders observed in women.”  

For their next steps, the researchers will work on further optimizing MUSIC so that they can use it to identify factors—such as regulatory genes and gene circuits—that are responsible for the accelerated aging observed in specific brain cells. “Subsequently, we will devise strategies to impede the activity of these genes or circuits, in the hopes of mitigating brain aging,” said Zhong.

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