Targeting Super Enhancers for Rheumatoid Arthritis Treatments

A link between gene regulatory elements and autoimmune diseases has been identified and can pave way for rheumatoid arthritis (RA) medication research, according to findings published in Nature.

Researchers from the National Institutes of Health believed they could identify what changes were made from newly identified cell enhancers called super enhancers (SE). The alterations were responsible for dictating the function and identity of each cell type, but the researchers believed they were also responsible for the malfunction of cells. The research team started by examining the SEs of T cells, which are known to play an important role in RA, because they thought SEs could display what RA risk factors were.

“Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” senior author John J. O’Shea, MD, said in a press 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.”

The researchers examined the mice model’s T cell genome for regions that are particularly susceptible to proteins using genomic techniques. There were several hundred regions that were identified by the researchers. The researchers further learned that the regions essentially control the activities of genes that encode cytokine and cytokine receptors, which aid communication between T cells and other cells. Cytokine and cytokine receptors also are responsible for immune response and defenses in the body.

Most importantly, the researchers learned that alterations associated with autoimmune diseases are localized to the T cell SEs, especially in RA. When human T cells were exposed to RA treatment tofacitinib, the activities of genes controlled by SEs were significantly affected compared to other genes without the SE activity. The researchers theorize that tofacitinib can bring therapeutic effects by interacting with SEs to change the activities of important T cell genes.

“Three types of data — the genetics of RA, a genomic feature of T cells, and the pharmacological effects of an RA drug — are all pointing to the importance of super-enhancers,” lead author Golnaz Vahedi, PhD continued in the statement. “These regions are where we plan to search for insights into the mechanisms that underlie RA and other autoimmune diseases, and for novel therapeutic targets for these conditions.”