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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：
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
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/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

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.

项目总结