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

摘要 原发性干燥综合征(PSS)在美国140万人中发生，是女性中最多的- 主要的自身免疫性疾病，男女比例为14：1。而性染色体已经 为了影响PSS中的女性偏见，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。 为了弥合这一知识鸿沟，本项目重点研究控制表达的调控机制 在逃脱者中，逃脱X染色体失活(XCI)的基因，在小唾液腺来源的间充质中 基质细胞(MSCs)。有趣的发现是，逃亡者在PSS中表现出明显的倾斜，但没有控制MSCs 强调了保持等位基因平衡在预防PSS发病中的重要性。因此， 本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。 该项目将检验中心假设，即miR6891-5P(一种人类白细胞抗原编码的非编码RNA)的调节失调， 导致Sjögren综合征患者偏离XCI： 目的1.阐明恢复miR6891-5p表达逆转X偏斜的功能后果 和PSS MSCs的炎性分化。 目的：建立miR6891-5p调节XCI逃逸的分子机制。 目的3.确定miR6891-5p调控的XCI逃逸的遗传和表观遗传交互作用。 这个项目将让我们深入了解与PSS相关的X染色体的分子基础 PSS中的异常及其对女性偏见的贡献。通过将miR6891-5P确立为关键 这项工作将为治疗PSS和其他疾病提供一个新的临床靶点。 自身免疫性疾病。

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.