Understanding the role of Epigenetic Reader SP140 in IBD

项目摘要/摘要 遗传因素是炎症性肠病(IBD)易感性的基础，但发病率的快速上升以及 低符合率，表明环境的普遍作用，可能还有表观基因组。 表观遗传酶的失调在癌症中是一个反复发生的前哨事件，使蛋白质“写”， “擦除”和“读取”表观基因组在药物发现中最有希望和最专注地追求的一些目标 今天。尽管如此，关于改变的表观遗传酶是如何起作用的几乎一无所知。 免疫紊乱，包括IBD。拟议研究的长期目标是确定如何 表观遗传改变影响IBD并准确破译致病机制以更好地 治疗策略。斑点蛋白140(SP140)是一种表观遗传的具有免疫限制性的“阅读”蛋白 表情。SP140单核苷酸多态与克罗恩病(CD)相关(1，2) 然而，SP140的功能和SP140 SNPs的后果仍不清楚。我们找到了CD- 相关的SP140 SNP导致SP140 mRNA剪接改变和SP140蛋白丢失(4)。我们也 确认SP140是巨噬细胞转录程序的关键协调者，对细胞身份至关重要 和功能(4)。此外，我们还发现，Sp140在小鼠体内的造血细胞枯竭加剧了结肠炎和 由于遗传变异导致的SP140丢失导致了CD的一个子集，其特征是先天抑制 豁免(4)。本提案的总体目标，这是实现我们的 长期目标是利用来自IBD遗传学联盟的多种资源来准确定义 SP140在介导对共生微生物的保护性先天免疫和获得性免疫中的作用 确定SP140的常见或罕见变体如何影响这些指定的功能。 在令人信服的初步数据的指导下，我们的假设将在三个具体目标上进行检验：1)阐明 SP140在保护共生微生物天然免疫中的作用；2)确定SP140在 B细胞的发育和功能；3)确定SP140作为表观遗传调节因子的机制。在……下面 第一个和第二个目标，我们将利用我们在小鼠身上诱导的SP140耗竭系统，并在平行试验中 携带SP140变异体的患者的细胞。对于目标3，我们将确定精确的机制， SP140调节免疫细胞的特性和功能。申请人认为，这种方法是创新的 因为这项工作将是对改变的表观遗传酶的表达和功能的首批描述之一 免疫介导性疾病的驱动力。这项拟议的研究意义重大，因为SP140变种 与CD、MS和CLL相关，因此了解SP140的功能将有助于理解和 这些疾病的分层。归根结底，这样的知识具有垂直发展的潜力 开发治疗CD和其他免疫疾病的新疗法。

Project Summary/Abstract Genetics underlie susceptibility to inflammatory bowel disease (IBD) but the rapid rise in incidence, as well as low concordance rates, point to a prevalent role for the environment and possibly the epigenome. Dysregulation of epigenetic enzymes is a recurrent and sentinel event in cancer, making proteins that “write”, “erase” and “read” the epigenome some of the most promising and intently pursued targets in drug discovery today. Despite this, virtually nothing is known about how altered epigenetic enzymes contribute to immunological disorders, including IBD. The long-term goal of the proposed research is to determine how epigenetic alterations influence IBD and accurately decipher the disease-causing mechanisms for better therapeutic strategies. Speckled Protein 140 (SP140) is an epigenetic “reader” protein with immune-restricted expression. Single nucleotide Polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD) (1, 2) however, the function of SP140 and the consequences of SP140 SNPs have remained unclear. We found CD- associated SP140 SNPs resulted in altered SP140 mRNA splicing and a loss of SP140 protein (4). We also identified SP140 as a key orchestrator of macrophage transcriptional programs essential for cellular identity and function (4). Furthermore, we found that hematopoietic depletion of Sp140 in mice exacerbated colitis and a loss of SP140 due to genetic variation contributed to a subset of CD characterized by suppressed innate immunity (4). The overall objective of the present proposal, which is the next step towards attainment of our long-term goal, is to utilize multiple resources from the IBD Genetics Consortium to precisely define the roles of SP140 in mediating protective innate and adaptive immunity toward commensal microorganisms, and determine how common or rare variants of SP140 impacts these ascribed functions. Guided by compelling preliminary data, our hypotheses will be tested in three specific aims: 1) Elucidate the role of SP140 in protective innate immunity toward commensal microorganisms; 2) Define the role of SP140 in B cell development and function; and 3) Determine the mechanism of SP140 as an epigenetic regulator. Under the first and second aims we will utilize our inducible SP140 depletion system in mice and in parallel examine cells from patients carrying SP140 variants. For aim 3 we will determine the precise mechanism by which SP140 regulates immune cell identity and function. The approach is innovative in the applicant's opinion because the work will be one of the first descriptions of altered epigenetic enzyme expression and function as a driver of immune-mediated disease. The proposed research is significant because SP140 variants are associated with CD, MS and CLL so understanding the function of SP140 will aid understanding of, and stratification of, these diseases. Ultimately, such knowledge has the potential to vertically advance development of novel therapeutics for CD and other immune disorders.