T cell histone GlcNAcylation participates in the epigenetics of lupus ABSTRACT Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that affects women ten times more often than men. Altered T cell signaling links genetic and environmental factors and contributes to disease etiopathogenesis. DNA methylation, histone modification, and miRNA regulate gene expression and chromatin structure by modifying the epigenome. DNA methylation suppresses gene transcription and in SLE, the female inactive X-chromosome is hypomethylated, which causes overexpression of genes that predispose females to lupus. SLE is also characterized by global T cell DNA hypomethylation that causes overexpression of immune- related genes and subsequent autoimmunity. We recently found that OGT (O-linked N-acetylglucosamine transferase), an X-linked gene, is overexpressed in female lupus T cells. OGT reversibly adds -N-acetyl-glucosamine (O-GlcNAc) to serine and threonine residues of proteins competing with phosphorylation. This makes OGT a regulator of cell signaling and transcription. Interestingly, GlcNAcylated protein levels are increased in female, but not male, T cell lupus patients, which correlate with OGT overexpression. Furthermore, O-GlcNAc is considered part of the histone code, and OGT regulates O-GlcNAcylation of histones. Histone 2B (H2B) is GlcNAc at Ser 112, a modification that facilitates H2BK120 ubiquitination required for transcriptional activation. Additionally, Ten Eleven Translocation enzymes TET2 and TET3 interact directly with OGT and co-localize on chromatin at active promoters. The effects of OGT in signaling pathways and on chromatin structure of T cells are unknown but may play an important role in T cell dysfunction in lupus as well as autoimmunity in general. We hypothesize that OGT overexpression in female lupus T cells modifies signaling pathways and DNA- histone binding profiles by O-GlcNAc of protein targets and chromatin remodelers. Hence, OGT may ultimately be an epigenetic modulator in lupus. To test this hypothesis, we propose to use proteomic and genetic approaches to: 1) Identify molecular targets of OGT, which are key proteins in T cell signaling that may contribute to the pathogenesis of lupus; 2) Determine whether overexpression of OGT in CD4 T cells results in altered glycosylation of histone proteins; and 3) Examine the effects of H2B modifications on gene regulation in cells that overexpress OGT This study will uncover abnormalities in T cell pathways and changes in gene regulation in SLE caused by OGT, a gene aberrantly expressed in female lupus T cells that may predispose females to the disease. By identifying new biomarkers and targets this project will serve as the foundation for future studies aimed at improving therapies for patients suffering from SLE and potentially other autoimmune diseases.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disease, which affects women ten times more often than men. The prevalence of lupus in the United States approaches 1 to 2 million people and 5 million people worldwide, according to the Lupus Foundation of America. Current treatments are based on immunosuppressive medications, which are unspecific and often toxic. As a result, patients can develop recurrent infections due to the generalized state of immunosuppression, which increases the risk of complications and mortality. Our studies will not only provide new insights into lupus etiopathogenesis but also identify new biomarkers for developing more specific therapies with fewer side effects than those of current therapies. Our results may also apply to other autoimmune diseases such as diabetes, in which O-glycosylation also plays an important role. In the long term, our studies will enable SLE patients to achieve a better quality of life.
