Researchers from the National Institutes of Health (NIH) recently published a study in the journal Nature on a series of genetic elements in specific immune cells and their link with immune system regulation and susceptibility to autoimmune diseases. The study is entitled “Super-enhancers delineate disease-associated regulatory nodes in T cells.”
Autoimmune disorders are characterized by an overreaction of the body’s own immune system that leads to the attack of healthy tissues, such as joints and organs, resulting in inflammation. Different tissues are affected in several autoimmune diseases; for instance, in rheumatoid arthritis the joints become swollen and inflamed, while in multiple sclerosis the brain and spinal cord are attacked. The causes underlying autoimmune diseases are poorly understood, but genetics are thought to play a crucial role.
The identification of genes that may cause susceptibility to autoimmune diseases can be challenging, since in the majority of cases the disorder is caused by a combination of genetic and environmental factors. Genetic studies revealed the presence of unique variants in people with autoimmune diseases; however, most of these genetic alterations are in DNA regions that do not correspond to genes, making it harder to explain their link with disease development. Researchers have suggested that these variants could be present in DNA elements called enhancers, which are known to behave like switches controlling the activity of genes.
Researchers led by Dr. John O’Shea, the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), have hypothesized that the genetic alterations are present within a new type of enhancer element named super-enhancer (SE). These SE have been shown to act as powerful switches, capable of controlling genes crucial to the identity and proper functioning of the cell. A considerable number of genetic variants associated with diseases were found within SE elements, indicating that the disease onset could be related to the malfunction of these switches.
The team searched for SEs in T cells, which are important in rheumatoid arthritis. “Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” explained Dr. O’Shea in a news release. “From the locations of their super-enhancers, T cells are telling us 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.”
Through genomic techniques, the team screened the genome of T cells for DNA regions carrying SEs. Several hundreds were identified and found to regulate the activity of genes related to cytokines (small signaling molecules), which are essential for T cell function, as they allow the communication between T cells and other cells to initiate an immune response. Remarkably, the team found that many of the previously identified genetic variants linked to rheumatoid arthritis and other autoimmune disease were located within these T cell SEs. When T cells were treated with the inhibitor tofacitinib (a drug approved for the treatment of rheumatoid arthritis), the activities of genes controlled by SEs were greatly affected, suggesting that the therapeutic action of this drug might be in part linked to the effect exerted on SEs, altering the activity of important T cell genes.
“Three types of data – the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug – are all pointing to the importance of super-enhancers,” added the study’s lead author Dr. Vahedi. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”
The team concluded that SEs play a crucial role in rheumatoid arthritis, and believe that their findings can help in the development of drugs and personalized medicine for people suffering with autoimmune diseases.
“We now know more about the genetics of autoimmune diseases,” noted NIAMS Director Dr. Stephen Katz. “Knowledge of the genetic risk factors helps us 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.”