Discovering miR6891-5p: guardian of XX allelic balance and barrier to Sjögren’s syndrome pathogenesis

发现 miR6891-5p：XX 等位基因平衡的守护者和干燥综合征发病机制的障碍

• 批准号: 10767679
• 负责人: Yun Liang
• 金额: $ 19.35万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767679
• 关键词: Address; Affect; Alleles; Allelic Imbalance; Autoimmune; Autoimmune Diseases; Autoimmunity; Cell Differentiation process; Characteristics; Chromosome abnormality; Clinical; Clinical Management; Clinical Pathways; Complex; Data; Data Set; Deposition; Development; Disease; Disease susceptibility; Ensure; Epigenetic Process; Equilibrium; Exhibits; Female; Gatekeeping; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Heterochromatin; Histone H3; Homeostasis; Hormonal; Inflammation; Inflammatory; Knowledge; Link; Lysine; Mediating; Methylation; Minor salivary gland structure; Molecular; Nuclear; Organ; Pathogenesis; Patients; Perimenopause; Persons; Phenotype; Polycomb; Process; Property; Proteins; RNA; Regulation; Risk Factors; Role; Salivary Glands; Sex Bias; Sex Chromosomes; Sex Differences; Sjogren' s Syndrome; Somatic Cell; Testing; Tissues; Transcript; United States; Untranslated RNA; Woman; Work; X Chromosome; X Inactivation; autoimmune pathogenesis; design; genomic locus; immunoregulation; insight; male; men; mesenchymal stromal cell; non-genetic; novel; pharmacologic; pre-clinical; prevent; self-renewal; sex; sexual dimorphism; success; targeted treatment; transcriptomic profiling

ABSTRACT Primary Sjögren's syndrome (pSS), occurring in 1.4 million people in the United States, is the most female- predominant autoimmune disease with a female-to-male ratio of 14:1. While the sex chromosome has been proposed to impact the female bias in pSS, the exact molecular mechanism of X chromosome regulation in pSS- relevant tissues remains elusive. To close this knowledge gap, this project focuses on the regulatory mechanisms controlling the expression of escapees, genes that escape X-chromosome inactivation (XCI), in minor salivary gland-derived mesenchymal stromal cells (MSCs). The intriguing finding that escapees exhibit marked skewing in pSS but not control MSCs underscores the importance of maintaining allelic balance in preventing pSS pathogenesis. Therefore, the objective of this project is to elucidate the molecular checkpoints ensuring allelic balance of escapee expression. The project will test the central hypothesis that dysregulation of miR6891-5p, a HLA-encoded noncoding RNA, leads to skewed escape from XCI in Sjögren's syndrome: Aim 1. Elucidate the functional consequence of restoring miR6891-5p expression in reversing X skewing and inflammatory differentiation of pSS MSCs. Aim 2. Establish the molecular mechanism by which miR6891-5p regulates escape from XCI. Aim 3. Determine the genetic and epigenetic interplay of miR6891-5p-regulated XCI escape. This project will allow us to gain insights into the molecular underpinnings of pSS-associated X chromosomal abnormalities as well as their contribution to the female bias in pSS. By establishing miR6891-5p as a critical gatekeeper against X skewing, this work will provide a novel clinical target for the treatment of pSS and additional autoimmune diseases.

抽象的 在美国有140万人发生的主要Sjögren综合征（PSS）是女性最多的 女性与男性比率为14：1的主要自身免疫性疾病。虽然性染色体已经 提议影响PSS中的女性偏见，PSS中的X染色体调节的确切分子机制 相关的组织仍然难以捉摸。 为了缩小这一知识差距，该项目重点介绍控制表达的调节机制 逃脱的基因逃脱X染色体灭活（XCI），在小唾液腺衍生的间充质中 基质细胞（MSC）。逃避裸露的明显偏斜的有趣发现，但不能控制MSC 强调了在预防PSS发病机理中保持等位基因平衡的重要性。因此， 该项目的目的是阐明分子检查点，以确保Escapee表达的等位基因平衡。 该项目将检验中心假设，即MiR6891-5p的失调（HLA编码的非编码RNA）的失调， 导致偏离Sjögren综合征XCI的偏离： 目标1。阐明恢复miR6891-5p表达的功能后果 PSS MSC的炎症分化。 目标2。建立MiR6891-5p调节XCI逃脱的分子机制。 目标3。确定miR6891-5p调节的XCI逃逸的遗传和表观遗传相互作用。 该项目将使我们能够深入了解PSS相关X染色体的分子基础 异常及其对PSS女性偏见的贡献。通过建立mir6891-5p作为关键 看门人反对X偏斜，这项工作将为PSS的治疗和其他 自身免疫性疾病。