PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-organ inflammation, resulting from loss of tolerance to self-antigens and production of anti-nuclear antibodies by activated, autoreactive B cells. To date, the exact etiology of SLE has not been well characterized. There is no cure for SLE and current treatments focus on controlling symptoms and minimizing flare-ups. Identification of new targets for therapy could greatly improve the therapeutic landscape for a disease for which little progress has been made in decades. In recent years, genome-wide association studies (GWAS) have been used to identify genetic risk factors for SLE. Interestingly, most single nucleotide polymorphisms (SNPs) identified through GWAS reside in non-coding regions, with some found in the poorly understood regulatory elements known as long-noncoding RNAs (lncRNAs). Our lab has significant experience in identifying and characterizing lncRNAs associated with human inflammatory diseases, and in the current study, we propose to characterize a novel SLE-associated lncRNA, that we have named as lnc12. Our preliminary studies have shown that lnc12 is highly expressed in germinal center B cells and appears to regulate a subset of genes known to be dysregulated during SLE progression. As determined by GWAS, lnc12 overlaps with a haplotype block of SNPs associated with SLE, including a highly associated SNP, rs4917014, which has been linked to susceptibility, cytokine levels, and clinical features in SLE. The rs4917014 SNP has been studied by other groups for potential effects on a neighboring gene, Ikaros family zinc finger 1(IKZF1), which encodes the critical B cell transcription factor, Ikaros. Increased expression of IKZF1 has been reported in patients with SLE, and interestingly, we have observed that lnc12 can bind to the gene promoter and 3’UTR of IKZF1, as well as members of the transcription machinery and spliceosome complex. We hypothesize that lnc12 regulates gene expression in B cells through its effects on IKZF1, and that changes in lnc12 expression, e.g. due to the SLE-associated rs4917014 SNP, may dysregulate IKZF1 expression and contribute to SLE pathogenesis. In Aim 1, we will probe the molecular mechanisms by which human lnc12 affects IKZF1 activity. In Aim 2, we will examine the physiological roles of lnc12 in B cell development and activation in vivo in a mouse model of SLE.

PROJECT NARRATIVE Systemic lupus erythematosus (SLE) is an incurable chronic autoimmune disease that is characterized by multiorgan inflammation and presents with a wide range of symptoms, ranging from mild to life-threatening. Genome-wide association studies (GWAS) have implicated a number of single-nucleotide polymorphisms (SNPs) with disease, including many that colocalize with long non-coding RNAs (lncRNAs). In the current study, we propose to characterize a novel SLE-associated lncRNA (lnc12) and determine how it might contribute to the pathogenesis of SLE.