T Cell Histone Glcnacylation Participates in the Epigenetics of Lupus

T 细胞组蛋白糖酰化参与狼疮的表观遗传学

• 批准号: 9459712
• 负责人: Gabriela Judith Gorelik
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9459712
• 关键词: Cell; Histone; Glcnacylation; Participates; Epigenetics

 DESCRIPTION (provided by applicant): 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 ß-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.

 描述(申请人提供)：T细胞组蛋白GlcN酰化参与狼疮的表观遗传学摘要系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病，女性的发病率是男性的10倍。T细胞信号改变将遗传和环境因素联系在一起，并有助于疾病的发病机制。DNA甲基化、组蛋白修饰和miRNA通过修饰表观基因组来调节基因表达和染色质结构。DNA甲基化抑制基因转录，在SLE中，女性不活跃的X染色体低甲基化，这导致女性易患狼疮的基因过度表达。系统性红斑狼疮的特征还包括全球T细胞DNA低甲基化，导致免疫相关基因的过度表达和随后的自身免疫。我们最近发现X连锁基因OGT在女性狼疮T细胞中高表达。OGT可逆地将N-乙酰氨基葡萄糖(O-GlcNAc)添加到与磷酸化竞争的蛋白质的丝氨酸和苏氨酸残基上。这使得OGT成为细胞信号和转录的调节器。有趣的是，女性T细胞狼疮患者的GlcNacylated蛋白水平升高，而男性患者则不是，这与OGT过度表达有关。此外，O-GlcNAc被认为是组蛋白编码的一部分，OGT调节组蛋白的O-GlcN酰化。组蛋白2B(H2B)是位于Ser112的GlcNAc，这是一种促进转录激活所需的H2BK120泛素化的修饰。此外，10个11个易位酶TET2和TET3直接与OGT相互作用，并共同定位在活性启动子的染色质上。OGT在信号通路和T细胞染色质结构中的作用尚不清楚，但可能在狼疮T细胞功能障碍和自身免疫中发挥重要作用。我们假设OGT在女性狼疮T细胞中的过度表达通过蛋白质靶标和染色质重构体的O-GlcNAc改变了信号通路和DNA-组蛋白结合谱。因此，OGT最终可能是狼疮的表观遗传学调节因子。为了验证这一假说，我们建议使用蛋白质组学和遗传学方法：1)确定OGT的分子靶点，这是T细胞信号中的关键蛋白质，可能有助于狼疮的发病；2)确定OGT在CD4T细胞中的过度表达是否导致组蛋白糖基化的改变；以及3)检测H2B修饰对过度表达OGT细胞中基因调控的影响。这项研究将揭示OGT引起的T细胞途径的异常和SLE基因调控的变化，OGT是一种在女性狼疮T细胞中异常表达的基因，可能使女性易患上狼疮。通过识别新的生物标记物和靶标，该项目将成为未来研究的基础 旨在改善SLE患者和潜在的其他自身免疫性疾病患者的治疗方法。