The new technology identifies the molecular properties of cells and maps their location within tissues

An ongoing effort to create detailed molecular atlases of individual cells in various tissues aims to better understand how diseases develop. Now, a team of researchers from Yale and Karolinska Institutet have developed a technology that brings this goal one step closer.

How cells in tissues function depends on their local environment. Mapping the molecular properties of cells while acquiring their precise location within a tissue is essential for a better understanding of disease. Rong Fan, professor of biomedical engineering at Yale, and Goncalo Castelo-Branco, professor of glial cell biology at the Karolinska Institute, led a team of researchers in developing a new technology to do just that. It allows them to determine which regions of chromatin—the complex of DNA and proteins packaged inside a cell’s nucleus—are accessible genome-wide in cells at specific locations in a tissue.

This chromatin accessibility is required for genes to be activated, which then provides unique insights into the molecular status of any given cell. Combining the ability to analyze chromatin accessibility with the spatial location of cells is a major breakthrough that could improve our understanding of cell identity, cellular state, and the underlying mechanisms that determine gene expression—known as epigenetics—in the development of tissues or different diseases. The results were published today Nature.

“We can now identify cell types to build a spatial cell atlas based on chromatin accessibility,” Fan said. “We can directly look at cell types at an epigenetic level either for better definition of cellular states or detection of cell types.”

The researchers profiled mouse and human tissues using a technique known as space-ATAC-seq. Applying this technique to brain tissue revealed the complex process of development of different brain regions. They also applied it to human tonsil tissue, which provided insights into the organization of immune cell types.

“We will get an unbiased global view and a much finer resolution view of all possible cellular states, and more importantly, ‘see’ where they are in a tissue,” Fan said. “It is a powerful tool for building cell maps and cell atlases.”

Yanxiang Deng, a postdoctoral fellow in Fan’s lab and lead author of the study, said that using the new method, they were able to identify the epigenome of cell types in mouse brain tissue at their location of birth.

“The spatial application of ATAC-Seq to diseased tissues may in the near future allow us to identify transitions between epigenetic states in specific cells in the context of the disease area, which will provide insight into the molecular mechanisms that mediate the acquisition of states pathological cells,” added Castelo-Branco.

An ambitious global initiative has been undertaken to define all the different types of cells in all human organs and different types of tissues. Single-cell sequencing has been critical to this effort, but it is difficult to map the location of cell types in the original tissue environment. This work for the first time enables the direct observation of cell types in a tissue as determined by the global epigenetic state.