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3-D Genome Mapping Uncovers Possible Treatment Targets in Lupus
shafere1 [at] email.chop.edu (By Emily Shafer)
A new method of mapping the genome in 3-D led researchers at Children’s Hospital of Philadelphia to discover two kinases that play a role in systemic lupus erythematosus, which now are potential treatment targets for the disease.
Previous genome-wide association studies (GWAS) identified more than 60 loci, or regions of the genome, that are associated with lupus risk. Although this information is valuable, these loci are large blocks of genome that contain hundreds of potential variants that make a gene a “culprit” in disease susceptibility. These variants may not be in the gene itself, but located in the surrounding chromatin.
Andrew D. Wells, PhD, and Struan F. A. Grant, PhD, co-directors of the Center for Spatial and Functional Genomics at CHOP, led a team that used a spatial mapping technique to view the genome in 3-D, to see what genes are interacting with these disease variants in the open chromatin. They focused on follicular helper T cells, which play a known role in the development in lupus. The study appeared in Nature Communications.
“This is a huge step forward in understanding how genes are regulated in human cells, and how genetic variants associated with disease risk might contribute to cellular function and come together to make up that risk,” said Dr. Wells, who is also associate professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania.
Lupus is an autoimmune disease that causes inflammation and damage to organs, skin, and joints. It has no known cure, and it disproportionately affects women and racial minorities. In children, teens age 15 and older are the most affected group.
The Right Kind of Cell
The idea of measuring the 3-D structure of the genome is not new, but this is the first study that has focused on both lupus and on follicular helper T cells. Previous, similar studies used other types of blood cells.
“We chose an important cell type that directly contributes to the auto-antibodies that are formed in lupus patients,” Dr. Wells said. “The regulatory architecture of these cells is going to be different from other cell types readily sampled from the blood, and the connections between the variants and genes are different. You will get answers if you study blood T cells, but they won’t be the right answers.”
The researchers used cells collected from pediatric tonsils to conduct their analysis. They chose tonsil cells because they are bona fide follicular helper T cells that have been “caught in the act” of helping cells make antibodies. Dr. Wells noted that the tonsils used were not from patients with lupus, which enabled the researchers to evaluate the starting structure of how the variants are connected to genes. The idea is that people who eventually develop lupus are disease-free at some point, but their cellular structure is poised to cause lupus.
After applying the 3-D structural genomic maps to the follicular helper T cells, Drs. Wells and Grant and their team identified 393 variants that are in spatial proximity to genes and may play a role in regulating them. If looking at a one-dimensional model of the genome, about 90% of those variants would have been considered distant from the gene.
Potential Treatment Target
The model clarified known disease biology and implicated two new genes with no prior known role in lupus: the kinases HIPK1 and MINK1. Targeting these kinases in the follicular helper T cells inhibits production of IL-21, a cytokine involved in regulating antibody production.
“We wouldn’t have ever identified these targets if not for the map we made that led us to them,” Dr. Wells said. “We hope to partner with drug companies to develop treatments that might target these kinases to treat lupus.”
The researchers plan to create a transgenic mouse model in which the HIPK1 kinase is knocked out, and then study the susceptibility of those mice to various lupus models. They also seek to further understand the role of this kinase in the function of follicular helper T cells.
“The maps we’ve made have a lot of utility,” Dr. Wells said. “Our study is just one example of how 3-D genomic maps can be deployed to understand lupus. The information we obtained is relevant to other autoimmune disorders and for infectious diseases, as this is a cell type that is absolutely required for immunity to viruses and responses to vaccines.”
Dr. Wells and his team will compare the maps made in this study with the maps of other cell types to see how similar and different they are. In addition, they will be applying the maps to the GWAS data sets of other pediatric autoimmune disorders to compare the disease architectures and implicate new potential drug targets.
For more information about the study, read the CHOP press release.