Epigenetic regulations in Sjogern's syndrome

干燥综合征的表观遗传调控

• 批准号: 9604635
• 负责人: Brij B Singh
• 金额: $ 36.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9604635
• 关键词: Epigenetic; regulations; Sjogern; syndrome

Project Summary Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction (Sjogren's syndrome). Although no genes mutations have been identified that could explain the pathogenesis of Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction of apoptosis in salivary gland acinar cells could be the two major events that could lead to salivary gland destruction. However, the molecular mechanism involved in the activation of T cells and apoptosis of salivary acinar cells is not known. Interestingly, similar to other autoimmune diseases, females have been shown to be affected with SS more than their male counterparts, with greater than 90% of SS cases being diagnosed in women. One hypothesis to explain this gender difference is that loss of random X-chromosome inactivation could be the cause of this disease (since many genes involved in immune function are expressed on the X- chromosome); however, the reason for the loss of X-chromosome inactivation is not known in any autoimmune disease, including SS. Results obtained from our ongoing studies indicate that a series of key epigenetic changes are observed in SS patients. As a result transcription of a set of genes that are essential for controlling proper immune response may be decreased. In addition, loss of expression of XIST1 (that is critical for random X-chromosome inactivation) may lead to the activation of certain genes on the X- chromosome that increases T cell activation, and initiates apoptosis. Furthermore, most of the loss of methylation on the X-chromosome was found in the CpG islands, which could lead to chromosomal instability and loss of imprinting. To further understand the mechanism, we performed a global RNA seq analysis on control and SS samples and have identified that a master regulator gene ELF4 that is present on the X- chromosome was upregulated (due to loss of X-chromosome inactivation) and could assist in the pathology of SS. These results are novel, and suggest a strong epigenetic origin for SS, but they need to be further validated. Therefore, in this grant proposal we intend to thoroughly characterize the role of epigenetic changes in salivary gland destruction and to determine the relationship between abnormal methylation and X- chromosome inactivation. The hypothesis of this study is that epigenetic changes along with the loss of X- chromosome inactivation alters ELF4 that increases susceptibility to immune changes and promote apoptosis of acinar cells, thereby leading to salivary gland destruction. Thus, identification of the mechanism as well as the pathways that lead to salivary gland destruction could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of inhibiting epigenetic changes in order to protect against salivary gland destruction. The results of our studies are expected to provide new insights into the role of epigenetic changes and the molecular mechanism involved in salivary gland destruction. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions and Sjögerns patients.

项目概要 唾液具有许多极其重要的生物功能，有助于维持口腔功能。 据估计，美国有超过 500 万人患有唾液腺功能障碍。 （干燥综合征）虽然尚未发现可以解释发病机制的基因突变。 干燥综合征 (SS) 的发生，最近的证据表明 T17 细胞浸润并诱导 唾液腺腺泡细胞凋亡可能是导致唾液腺损伤的两个主要事件 然而，其分子机制涉及T细胞的激活和唾液细胞凋亡。 腺泡细胞不对称，与其他自身免疫性疾病相似，女性已被证明是对称的。 SS 患者多于男性，超过 90% 的 SS 病例是在 解释这种性别差异的一个假设是 X 染色体随机失活的丧失。 可能是这种疾病的原因（因为许多涉及免疫功能的基因在X-上表达） 染色体）；然而，X 染色体失活的原因尚不清楚。 自身免疫性疾病，包括 SS。我们正在进行的研究获得的结果表明，一系列关键因素 在 SS 患者中观察到表观遗传变化，这是一组重要基因转录的结果。 此外，XIST1 表达的丧失可能会降低。 对于随机 X 染色体失活至关重要）可能会导致 X 染色体上某些基因的激活 增加 T 细胞活化并引发细胞凋亡的染色体，此外，大部分丢失。 在 CpG 岛中发现 X 染色体上的甲基化，这可能导致染色体不稳定 为了进一步了解该机制，我们对RNA进行了全局分析。 对照和 SS 样本，并已鉴定出存在于 X 上的主调控基因 ELF4 染色体上调（由于 X 染色体失活的损失）并且可能有助于病理学 SS。这些结果是新颖的，表明 SS 具有很强的表观遗传起源，但还需要进一步研究。 因此，在这项拨款提案中，我们打算彻底描述表观遗传学的作用。 唾液腺破坏的变化并确定异常甲基化与 X- 之间的关系 本研究的假设是表观遗传随着 X- 的丢失而发生变化。 染色体失活会改变 ELF4，从而增加对免疫变化的敏感性并促进细胞凋亡 腺泡细胞，从而导致唾液腺破坏，从而确定其机制。 导致唾液腺破坏的途径可以作为唾液腺中的药物靶标 我们将协调我们的努力，以确定抑制的功能意义。 我们的研究结果是为了防止唾液腺破坏而发生表观遗传变化。 有望为表观遗传变化的作用和涉及的分子机制提供新的见解 更好地了解这些事件对于阐明新疗法非常重要。 适用于唾液腺功能障碍和 Sjögerns 患者。