Expression of X-linked autoimmunity genes in B cells during female-biased autoimmunity

女性偏向性自身免疫期间 B 细胞中 X 连锁自身免疫基因的表达

• 批准号: 9391172
• 负责人: Montserrat C Anguera
• 金额: $ 20.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391172
• 关键词: Activated Lymphocyte; Affect; Age; Animals; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Cell Lineage; Cells; Characteristics; Childhood; Chromatin; Chromosomes; Chronic Disease; Complex; Data; Development; Disease; Disease Progression; Epigenetic Process; Etiology; Female; Future; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Transcription; Heterochromatin; Human; Hyperactive behavior; Immune system; Immunity; Immunologist; Impairment; Individual; Injections; Intervention; Kidney; Link; Lupus; Lymphocyte; Mammals; Mediating; Modeling; Modification; Molecular Abnormality; Mus; Nephritis; Organ; Pathogenesis; Pathology; Patients; Peripheral; Play; Population; Pristane; Process; Production; RNA; Race; Research Proposals; Resolution; Role; Severities; Severity of illness; Sex Chromosomes; Socioeconomic Status; Somatic Cell; Symptoms; System; Systemic Lupus Erythematosus; TLR7 gene; Testing; Therapeutic; Tissues; Untranslated RNA; Woman; X Chromosome; X Inactivation; associated symptom; clinical material; defined contribution; disorder risk; experimental study; gene function; high risk; insight; interest; lupus-like; male; mouse model; novel; overexpression; public health relevance; recruit; sex; sex disparity; systemic autoimmune disease

Project Summary Autoimmune disorders affect 5-10% of the population and about 80% of these patients are women. Sex chromosomes appear to play an important role in autoimmunity, yet experiments demonstrating causality are missing. Autoimmune disorders like systemic lupus erythematosus (SLE) have no cure, and intervention strategies for correcting genetic abnormalities in lupus hold great promise. Genes from the sex-linked X- chromosome are commonly overexpressed in SLE and are thought to contribute to disease progression. Female mammals, who have 2 X chromosomes (XX), silence one X in a process called X-Chromosome Inactivation (XCI), thereby equalizing X-linked gene expression with males (XY). XCI is initiated and maintained by expression of the long noncoding RNA XIST. It is unknown whether increased X-linked gene expression in SLE results from enhanced transcription from the active X (monoallelic) or from reactivation of the inactive X (biallelic). Remarkably, we recently discovered that the inactive X in naïve lymphocytes lacks heterochromatin marks and XIST RNA localization, and upon stimulation, these epigenetic modifications return to the X in less than half of the transcriptionally active cells. This proposal will test the hypothesis that inefficient XIST RNA recruitment to the inactive X impairs the acquisition of heterochromatin marks, thereby increasing the potential for partial X-reactivation and abnormal overexpression of autoimmunity associated genes. We will also determine if biallelic expression of X-linked autoimmunity related genes is increased in pediatric SLE patients and predisposes female mice to develop SLE-like symptoms. Last, we will use our novel X-chromosome silencing system to determine if we can decrease the expression of X-linked genes that contribute to SLE. Our results, the first to define the contribution of XCI to autoimmunity, will provide insight into SLE pathogenesis and identify epigenetic mechanisms as future targets for SLE therapy.

项目摘要 自身免疫性疾病影响5-10%的人口，其中约80%的患者是女性。性 染色体似乎在自身免疫中起着重要作用，但证明因果关系的实验 失踪了自身免疫性疾病如系统性红斑狼疮（SLE）无法治愈， 纠正狼疮遗传异常的策略具有很大的希望。来自性连锁X染色体的基因 染色体上的蛋白质通常在SLE中过表达，并被认为有助于疾病进展。 雌性哺乳动物有两条X染色体（XX），在一个称为X染色体的过程中， 失活（XCI），从而使X连锁基因表达与雄性（XY）相等。XCI启动， 通过表达长的非编码RNA XIST来维持。目前尚不清楚增加的X连锁基因是否 在SLE中的表达是由于活性X（单等位基因）的转录增强或 非活性X（双等位基因）。值得注意的是，我们最近发现，幼稚淋巴细胞中的非活性X缺乏 异染色质标记和XIST RNA定位，并且在刺激后，这些表观遗传修饰返回 在不到一半的转录活跃细胞中，这一提议将检验以下假设： 无效的XIST RNA募集到失活的X会损害异染色质标记的获得， 增加了部分X-再激活和自身免疫相关的异常过度表达的可能性， 基因.我们还将确定X连锁自身免疫相关基因的双等位基因表达是否增加， 儿童SLE患者，并使雌性小鼠易于发展SLE样症状。最后，我们将使用我们的小说 X染色体沉默系统，以确定我们是否可以减少X连锁基因的表达， 有助于SLE。我们的研究结果首次定义了XCI对自身免疫的贡献， SLE发病机制和鉴定表观遗传机制作为SLE治疗的未来目标。