Ikaros mediated gene regulation in human systemic lupus erythematosus (BA4P.138)

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Genetic susceptibility and molecular aberrations create an abnormal T cell phenotype. One of the key components contributing to signaling defects in SLE pathogenesis is the serine threonine phosphatase (PP2A). The factors affecting expression of PP2A in SLE T cells thus warrant an extensive study. We have previously shown that the transcription factor Ikaros binds to a site in the first intron of PP2A and acts as a repressor of PP2A expression. Here, we build upon this key finding of a novel regulatory mechanism involved in the pathogenesis of SLE. This intronic Ikaros binding site in PP2A harbors a single nucleotide polymorphism. We report that Ikaros exhibits differential binding to this site. Using oligonucleotide binding assays as well as EMSA, we demonstrate defective binding of Ikaros to the site containing the SLE risk SNP as compared to WT sequence. Luciferase reporter assays show that promoter activity of PP2A is increased in presence of this SNP. We are further analyzing the recruitment of Ikaros to this site in individuals with either WT or the variant allele, to test our hypothesis that increased levels of PP2A observed in SLE patients is at least in part due to reduced Ikaros binding at this site. To conclude, we demonstrate that the repressor Ikaros binds with less avidity to a PP2A intronic SLE risk variant and allows increased PP2A expression, a key molecule in SLE pathogenesis.