Elucidating the Role of Dynamic X-Chromosome Inactivation Maintenance in the Pathogenesis of Systemic Sclerosis

阐明动态 X 染色体失活维持在系统性硬化症发病机制中的作用

基本信息

批准号：
10511513
负责人：
Montserrat C Anguera
金额：
$ 21.45万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511513
关键词：
Affect Attention Autoimmune Diseases Bleomycin CD3 Antigens CD8-Positive T-Lymphocytes CREST Syndrome CXCR3 gene Candidate Disease Gene Cell physiology Cells Cicatrix Collagen Cutaneous Cytology Data Defect Development Disease Embryonic Development Epigenetic Process Exhibits FOXP3 gene Female Fibrosis Fluorescent in Situ Hybridization Future Gene Dosage Gene Expression Gene Expression Profile Gene Expression Regulation Gene Silencing Genes Genetic Risk Genetic Transcription Goals Harvest Heterochromatin Hormonal Human IL13RA1 gene Immune Immune system Immunofluorescence Immunologic Impairment In Vitro Inflammation Investigation Knockout Mice Laboratories Link Lupus Lymphocyte Maintenance Mediating Modeling Modification Molecular Monozygotic twins Morbidity - disease rate Mus Nuclear Organ Outcome Pathogenesis Pathogenicity Pathology Patients Pattern Peripheral Predisposition Process Pulmonary Fibrosis RNA RNA Interference Rest Role Scleroderma Serum Sex Bias Skin Skin Tissue Somatic Cell Splenic Tissue Structure of parenchyma of lung Systemic Scleroderma T-Lymphocyte T-Lymphocyte Subsets TIMP1 gene TNFSF5 gene Testing Therapeutic Therapeutic Intervention Tissues Untranslated RNA Vascular Diseases Wild Type Mouse Woman Work X Chromosome X Inactivation base biological sex cell type cellular imaging comparative epigenetic regulation epigenetic silencing histone modification immune function improved insight male men mortality mouse model novel novel therapeutics overexpression peripheral blood prevent programs recruit risk variant single molecule skin fibrosis subcutaneous systemic autoimmune disease systemic autoimmunity transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract: Systemic sclerosis (SSc) is a systemic autoimmune disease that predominantly affects women and is associated with significant morbidity and mortality due to fibrosis of the skin and internal organs. The molecular origin of this striking female bias and its relationship to core aspects of the pathogenesis of SSc, including immune dysregu- lation, multiorgan fibrosis, and vasculopathy, remains unclear. While there are known genetic risk variants asso- ciated with SSc, the low monozygotic twin concordance rate has prompted investigation into the role of epige- netic dysregulation in its pathogenesis. Importantly, the X-chromosome contains several proinflammatory and profibrotic genes, and their appropriate expression in females is epigenetically regulated in part through X-chro- mosome inactivation (XCI), a female-specific epigenetic mechanism that silences one of the two X chromosomes in order to equalize X-linked gene dosage between XX females and XY males. XCI is maintained in somatic cells by a variety of epigenetic modifications that are enriched on the inactive X chromosome (Xi), including the long noncoding RNA XIST and additional heterochromatic histone modifications. We recently discovered that XCI maintenance in T-cells from both humans and mice is “dynamic.” In “dynamic XCI maintenance”, XIST RNA and heterochromatic marks are cytologically absent from the Xi in resting T-cells and subsequently relocalize to the Xi upon in vitro cellular activation. We have found that dynamic XCI maintenance is impaired in T-cells from women with lupus, another female-biased autoimmune disease, and is associated with aberrant X-linked gene expression from the Xi. Based on the well-established role of T-cells in SSc-mediated pathology, the number of X-linked proinflammatory and profibrotic genes, the aberrantly increased expression of many of these genes in SSc T-cells, and our preliminary data, we hypothesize that impaired dynamic XCI maintenance in T-cells is a pathogenic mechanism in SSc that accordingly contributes to the observed female bias. In Aim 1, we will use single cell imaging to determine whether XCI maintenance is impaired in T-cells from females with SSc. We will couple these analyses with transcriptomic studies to determine the contribution of the Xi to the observed X-linked gene expression profile. In Aim 2, we will induce scleroderma-like disease in a novel mouse model of impaired XCI maintenance to determine how impaired XCI maintenance in T-cells impacts T-cell-specific transcriptional programs conferring susceptibility to fibrosis in SSc-relevant organs. Collectively, this work has the potential to identify a novel epigenetic mechanism of female bias in SSc and will simultaneously identify which X-linked genes become aberrantly expressed in T-cells during the development of fibrotic disease. These findings will improve our understanding of how biological sex contributes to the pathogenesis of SSc and related female- biased autoimmune disease and may enable the eventual discovery of new therapies for SSc.

项目摘要/摘要：全身性硬化症（SSC）是一种全身性自身免疫性疾病，主要影响女性，并且与之相关由于皮肤和内部器官的纤维化而导致的发病率和死亡率很高。这个分子起源触及女性偏见及其与SSC发病机理的核心方面的关系，包括免疫失调 Lay，多器官纤维化和血管病仍然不清楚。尽管有已知的遗传风险变异低单卵双胞胎一致性率与SSC呈现，促使对发作的作用进行了研究。其发病机理中的网络失调。重要的是，X染色体包含几种促炎和纤维化基因及其在女性中的适当表达在表观上通过X-Chro-部分调节 Mosome灭活（XCI），一种女性特异性表观遗传机制，使两个X染色体之一沉默为了在XX女性和XY雄性之间均衡X连锁基因剂量。 XCI保持在体细胞中通过多种表观遗传修饰，这些修饰富集在无活性X染色体（XI）上，包括长非编码RNA XIST和其他异型组蛋白修饰。我们最近发现XCI 来自人类和小鼠的T细胞维护是“动态的”。在“动态XCI维护”中，Xist RNA和在静止的T细胞中，XI在细胞学上没有杂色标记，随后重新定位为体外细胞活化后的XI。我们发现动态XCI维护在T细胞中受到了损害狼疮的女性，另一种女性偏见的自身免疫性疾病，与异常的X连锁基因有关 xi的表达。基于T细胞在SSC介导的病理学中的公认作用，数量 X连锁的促炎和纤维化基因，许多这些基因在异常增加的表达 SSC T细胞和我们的初步数据，我们假设T细胞中动态XCI维护受损是一个 SSC中的致病机制促成了观察到的女性偏见。在AIM 1中，我们将使用单细胞成像以确定SSC女性的T细胞中XCI维持是否受损。我们将将这些分析与转录组研究进行近对，以确定XI对观察到的X连锁的贡献基因表达谱。在AIM 2中，我们将在新型的小鼠模型中诱导硬皮病样疾病 XCI维护以确定T细胞中XCI维护受损如何影响T细胞特异性转录计划会议会议对SSC相关器官中纤维化的易感性。总的来说，这项工作有可能确定SSC中女性偏见的新型表观遗传机制，将简单地识别哪个X连锁在纤维化疾病发展过程中，基因在T细胞中异常表达。这些发现会提高我们对生物性别如何有助于SSC和相关女性的发病机理的理解 - 自身免疫性疾病有偏见，并可能使SSC的新疗法发现事件。