Key Molecule in Lupus-linked Gene Identified, Opening New Therapy Possibilities

Yale researchers have discovered a new transcription factor governing the production of a gene related to conditions such as systemic lupus erythematosus (SLE). The discovery opens up the possibility of more personalized SLE treatment.

The study, titled “Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus“ and published in the Journal of Clinical Investigation, focused on a gene called MIF, coding for an immune molecule involved in regulating numerous aspects of immune responses. Mutations in the promoter of the gene — a region regulating gene expression — are involved not only in lupus but also other inflammatory diseases, such as rheumatoid arthritis, as well as in infectious diseases and cancer.

The mutations present in the MIF gene are called microsatellites and consist of five to eight repeats of a few DNA bases. More repeats give rise to higher levels of MIF protein.

The team, led by professor of medicine Dr. Richard Bucala, reproduced the mutant MIF gene in cultured cells in the lab and used a proteomics approach to screen the proteins interacting with the gene. This allowed them to identify a molecule binding to the gene at the site of the microsatellites. It turned out to be a transcription factor, molecules that bind to the DNA and regulate how active a gene is, allowing for more or less production of the protein produced by a given gene. The authors believe this transcription factor is interacting only with this gene, making it an ideal candidate for drugs targeting diseases associated with the MIF mutation.

In a press release, Dr. Bucala said, “Now that we know the exact transcription factor, we can begin to design drugs that will interfere specifically with the disease pathway. It opens the way for the most precise form of drug development that is possible.”

He added, “This deeper understanding of the gene’s variants and expression will lead to precision drug targeting based on an individual’s genetic profile. Knowing what the transcription factor is, presents the possibility of a real personalized medicine approach.”

The team is already studying drugs, now in clinical trials for cancer and autoimmunity, that target MIF.