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

基本信息

批准号：
9244999
负责人：
Montserrat C Anguera
金额：
$ 24.15万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/9244999
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 Genes Genetic Genetic Transcription Heterochromatin Human Hyperactive behavior Immune system Immunity Immunologist Impairment Individual Injection of therapeutic agent 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 Recruitment Activity 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 sex sex disparity systemic autoimmune disease

项目摘要

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.

项目概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。染色体似乎在自身免疫中发挥着重要作用，但证明因果关系的实验尚不清楚系统性红斑狼疮 (SLE) 等自身免疫性疾病无法治愈，也无法进行干预。纠正狼疮遗传异常的策略具有广阔的前景。染色体通常在 SLE 中过度表达，并被认为有助于疾病进展。雌性哺乳动物有 2 条 X 染色体 (XX)，在称为 X 染色体的过程中沉默一条 X 失活（XCI），从而使 X 连锁基因表达与雄性相等（XY）。是否通过长非编码 RNA XIST 的表达来维持 X 连锁基因的增加尚不清楚。 SLE 中的表达是由于活性 X（单等位基因）转录增强或重新激活值得注意的是，我们最近发现幼稚淋巴细胞中缺乏非活性 X。异染色质标记和 XIST RNA 定位，并且在刺激后，这些表观遗传修饰会返回该提案将检验以下假设：低效的 XIST RNA 募集到失活的 X 会损害异染色质标记的获得，从而增加部分 X 线再激活和自身免疫相关异常过度表达的可能性我们还将确定 X 连锁自身免疫相关基因的双等位基因表达是否增加。儿科 SLE 患者并使雌性小鼠容易出现 SLE 样症状最后，我们将使用我们的新型药物。 X 染色体沉默系统以确定我们是否可以减少 X 连锁基因的表达我们的研究结果首次定义了 XCI 对自身免疫的贡献，这将提供深入的见解。深入了解 SLE 发病机制，并确定表观遗传机制作为 SLE 治疗的未来目标。