Summary

By probing how DNA is packaged in single mouse cells, scientists have uncovered how different types of cells distinguish themselves. The resulting atlas could lead to clearer views of tissue development and how diseases take hold.

A powerful cell-barcoding technique has helped uncover the different ways in which the genome is packaged in about 100,000 individual mouse cells. This atlas, described by Howard Hughes Medical Institute Investigator Jay Shendure and colleagues, gives scientists a way to see which parts of the genome are active in any given cell.

The results, published August 2, 2018, in the journal Cell, could ultimately help scientists understand how diverse tissues develop and offer a window into diseases, says Shendure, a geneticist at the University of Washington. Already, his team has used the mouse atlas to highlight which types of cells play a role in human diseases such as bipolar disorder and Alzheimer’s.

Scientists have already read the entirety of both human and mouse genomes ­– the genetic instruction books for all the business a cell needs to accomplish. “But that’s not the whole picture,” Shendure says. He likens the genome to a cookbook carried by each cell. “Even though it’s the same cookbook, different meals are being made,” Shendure says. But “how does the genome in any given cell know which recipes to make?”

“How does the genome in any given cell know which recipes to make?”

Jay Shendure

One “cook me” signal is chromatin, which refers to how DNA is packaged in every cell. When DNA is wound into tight balls, cellular chefs can’t reach the genes buried inside. That means that those balled-up genes aren’t active. When this tight weave is relaxed, genes are reachable, and the cell can get busy. Such relaxed, “open” chromatin “helps instruct cells what recipes to produce,” Shendure says.

Along with University of Washington colleague Cole Trapnell, Shendure and his team devised a clever way to discern the chromatin landscape inside single cells. The researchers used an enzyme that flags only open chromatin. At the same time, the cells were also tagged with genetic barcodes. These barcodes let the scientists profile vast numbers of individual cells.

This single cell scrutiny turned up some surprises, Shendure says. Cells that line blood vessels, for instance, have very different patterns of open chromatin depending on where the blood vessels reside. Big differences exist among these cells, called endothelial cells, in the heart, lungs, and kidneys. It’s possible that the cells would need to turn on different genes in these different bodily contexts, he says.

In this study, the technology yielded a close look at about 100,000 cells taken from 13 tissues of an adult mouse. Earlier studies have examined patterns of open chromatin among cells in certain tissues. But those studies grouped cells together and averaged the results. By looking at the chromatin structure of individual cells, Shendure and his colleagues gained the ability to observe previously hidden diversity among cells in the same tissue.

But other cell types seem to be the same, no matter where in the body they live. Immune cells called macrophages, for example, had very similar patterns of open chromatin even though they came from different places.

Uncovering the variety among living cells is important, Shendure says, but “the most exciting thing about the paper” is the link between chromatin structure and disease. He and his colleagues linked mouse cells with similar patterns of open chromatin to genetic data on human diseases. Bipolar disease and Alzheimer’s were tied to specific types of mouse cells, links that could ultimately lead to a deeper understanding of how certain cells malfunction in these complex diseases.With this technique, researchers can now study how chromatin changes in certain diseases or over time. In a related study also appearing on August 2, 2018, in the journal Molecular Cell, Shendure, Trapnell, and colleagues used the technique to investigate how muscle cells develop, for instance.

Next, Shendure plans to apply the single cell technique more broadly. “We are excited about the prospects of generating similar datasets for other species – most importantly, humans,” he says.

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Darren A. Cusanovich, Andrew J. Hill et al., “A single-cell atlas of in vivo mammalian chromatin accessibility.” Cell. Published online August 2, 2018. doi: 10.1016/j.cell.2018.06.052

Hannah A. Pliner et al., “Cicero predicts cis-regulatory DNA interactions from single cell chromatin accessibility data.” Molecular Cell. Published online August 2, 2018. doi: 10.1016/j.molcel.2018.06.044

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