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屏障

• 批准号: 10424816
• 负责人: Yun Liang
• 金额: $ 23.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424816
• 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 susceptibility; Ensure; Epigenetic Process; Equilibrium; Exhibits; Female; Gatekeeping; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Histone H3; Homeostasis; Hormonal; Inflammatory; Knowledge; Link; Lysine; Mediating; Methylation; Minor salivary gland structure; Molecular; Nuclear; Organ; Pathogenesis; Patients; Perimenopause; Persons; Pharmacology; 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; base; design; genomic locus; hormone regulation; immunoregulation; insight; male; men; mesenchymal stromal cell; non-genetic; novel; pre-clinical; prevent; self-renewal; sex; sexual dimorphism; success; transcriptomics

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.

摘要 原发性干燥综合征（pSS），发生在140万人在美国，是最女性- 主要的自身免疫性疾病，男女比例为14：1。虽然性染色体已经被 提出影响pSS中的女性偏好，pSS中X染色体调控的确切分子机制- 相关组织仍然难以捉摸。 为了缩小这一知识差距，本项目的重点是控制表达的调控机制， 逃避者，逃避X染色体失活（XCI）的基因，在小唾液腺来源的间充质 基质细胞（MSCs）。有趣的发现是，逃逸者在pSS中表现出明显的偏斜，而在对照MSC中则没有。 强调了保持等位基因平衡在预防pSS发病机制中的重要性。因此 该项目的目的是阐明确保逃逸基因表达的等位基因平衡的分子检查点。 该项目将测试一个中心假设，即miR 6891 - 5 p（一种HLA编码的非编码RNA）的失调， 导致舍格伦综合征患者偏离XCI： 目标1.阐明恢复miR 6891 - 5 p表达在逆转X偏斜中的功能后果 和pSS MSC的炎性分化。 目标2.建立miR 6891 - 5 p调节XCI逃逸的分子机制。 目标3.确定miR 6891 - 5 p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， 异常以及它们对pSS中女性偏见的贡献。通过将miR 6891 - 5 p确定为关键的 这项工作将为pSS的治疗提供一个新的临床靶点， 自身免疫性疾病