Link between powerful gene regulatory elements and autoimmune diseases revealed

A team of researchers has discovered the genomic switches of a blood cell key to regulating the human immune system.

The findings of the National Institutes of Health have open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.

Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases and the causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families.

NIAMS Director Stephen I. Katz said that they now know more about the genetics of autoimmune diseases and knowledge of the genetic risk factors helps them assess a person's susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual."

Senior author John J. O'Shea's team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease.

O'Shea added that rather than starting off by looking at genes that they already knew were important in T cells, they took an unbiased approach. From the locations of their super-enhancers, T cells are telling them where in the genome these cells invest their assets, their key proteins, and thereby where we are most likely to find genetic alterations that confer disease susceptibility.

Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

When the scientists exposed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs to alter the activities of important T cell genes.

The study is published in Nature.