Defining function and regulation of the novel SLE-susceptibility gene ILRUN in T cells

About This Grant

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematous (SLE) causes substantial mortality and morbidity. Current treatments are not highly effective in modifying disease progression, especially in severely affected patients with renal involvement. Hence, there is a large unmet need to develop novel therapeutic targets. Genome-wide association studies (GWAS) offer an unbiased approach to identify genes that play an important role in driving disease pathogenesis. To identify risk genes in immune cell types relevant to SLE pathogenesis, we performed the first large-scale single-cell eQTL study on activated CD4+ T cells and found that SLE-risk variants were strongly associated with increased expression of the poorly understood gene ILRUN. Our study provides the first direct evidence that activated CD4+ T cells are the key cell types in which SLE-risk variants increase the expression of ILRUN. In Aim 1, we will identify the functional SLE-risk variants associated with ILRUN expression in activated CD4+ T cells. We will employ CRISPRi assays to determine functional enhancers that overlap ILRUN eQTLs, perform luciferase reporter assays to determine functional variants in ILRUN promoter and enhancers, and perform ChIP assays to identify the functional ILRUN eQTLs that directly perturb the binding of key transcription factors and modulate ILRUN expression. In Aim 2, we will assess the functional role of ILRUN in CD4+ T cells in the context of SLE and determine whether ILRUN influences the activation, apoptosis, proliferation, differentiation and cytokine production of CD4+ T cells. Overall, the studies examining the expression, regulation and function of ILRUN in CD4+ T cells will provide important mechanistic insights into the genetic basis of SLE.