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

项目摘要 自身免疫性疾病影响了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扮演着重要的角色，然而证明因果关系的实验是 失踪。自身免疫性疾病，如系统性红斑狼疮(SLE)，没有治愈和干预措施 纠正狼疮遗传异常的策略大有可为。性连锁X染色体的基因- 染色体在系统性红斑狼疮中通常过度表达，被认为与疾病的进展有关。 雌性哺乳动物有2个X染色体(XX)，在一个被称为X染色体的过程中，一个X染色体沉默 失活(XCI)，从而使X连锁基因的表达与雄性(XY)持平。XCI启动，并且 由长的非编码RNA XIST的表达维持。目前尚不清楚X连锁基因是否增加 SLE中的表达是活性X(单等位基因)转录增强或重新激活的结果 非活动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不活跃的X缺乏 异染色质标记和XIST RNA定位，在刺激下，这些表观遗传修饰返回 在转录活跃的细胞中，只有不到一半的细胞中存在X。这项提议将检验这样一个假设： 低效的XIST RNA招募到非活性X会损害异染色质标记的获得，从而 增加部分X-再激活和自身免疫相关异常过表达的可能性 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在 儿童系统性红斑狼疮患者，并使雌性小鼠容易出现类似系统性红斑狼疮的症状。最后，我们将用我们的小说 X染色体沉默系统来确定我们是否可以减少X连锁基因的表达 对系统性红斑狼疮有贡献。我们的结果首次定义了XCI对自身免疫的贡献，这将为我们提供洞察力 研究系统性红斑狼疮的发病机制，并确定表观遗传学机制作为未来SLE治疗的靶点。

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.