Scientists Map Network of Disease-Related Immune Genes
Using new technology to study thousands of genes simultaneously in immune cells, researchers at the Gladstone Institutes, UC San Francisco (UCSF), and the Stanford School of Medicine have created the most detailed map of how complex networks of genes function together. New insights into how these genes relate to one another shed light on the basic drivers of immune cell function and immune disease.
“These results help us refine a systematic network map that can serve as an instruction manual for how human immune cells function and how we can engineer them to our advantage,” says Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and senior author. from the new study, published in Nature Genetics.
The study, carried out in collaboration with Jonathan Pritchard, PhD, professor of genetics and biology at Stanford School of Medicine, is also important for better understanding how a person’s gene variation is linked to the risk of autoimmune disease.
Immunity Insights from CRISPR
Researchers know that when the immune system’s T cells — white blood cells that can fight infection and cancer — become active, the levels of thousands of proteins in the cells change. They also know that many proteins are interconnected so that a change in the level of one protein can cause a change in the level of another.
Scientists represent the relationship between these proteins and genes as a network that looks like a subway map. This tissue mapping is important because it can help explain why mutations in two different immune genes can cause the same disease, or how a drug can impact many immune proteins at once.
In the past, scientists have mapped parts of this network by deleting the genes for each protein, one at a time, and studying their impact on other genes and proteins, as well as the overall function of immune cells. But this kind of “downstream” approach reveals only half of the picture.
We really wanted to see what controls key immune genes.
“We really wanted to see what controls key immune genes,” says Jacob Freimer, PhD, a postdoctoral fellow in Marson and Pritchard’s lab, and first author of the new paper. “This kind of upstream approach has never been done before in primary human cells.”
This upstream approach would be like mapping subway routes by first identifying major hubs and then figuring out routes to those major stations, rather than painstakingly reconstructing the entire network from different satellite stations.
Freimer and his collaborators turned to the CRISPR-Cas9 gene-editing system, which allows them to disrupt thousands of genes at once. They concentrated on the genes that make a type of protein known as a transcription factor. Transcription factors are switches that activate or deactivate other genes and can control many genes at once. The scientists then studied the impact of this disruption of transcription factors on three immune genes known to play important roles in T cell function: IL2RA, IL-2, and CTLA4. These three genes are the hubs that anchor upstream mapping efforts.
“This allows us to trace over a thousand transcription factors and see which ones impact these immune genes,” Freimer said.
Connected Network
The researchers expected that they would find an association between the genes that regulate IL2RA, IL-2, and CTLA, but they were surprised by the level of connectivity they found. Among the 117 regulators found to control the level of at least one of the three genes, 39 controlled two of the three, and 10 regulators simultaneously altered the level of all three genes.
To help populate the immune gene map even more, the team next took a more traditional downstream approach, removing 24 designated regulators from T cells to show the full list of genes they regulate—in addition to IL2RA, IL-2, and CTLA4.
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