Roles of HDAC3 in Epidermal Langerhans Cell Ontogeny and Function

HDAC3 在表皮朗格汉斯细胞个体发育和功能中的作用

基本信息

批准号：
9222709
负责人：
QING-SHENG MI
金额：
$ 32.89万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9222709
关键词：
Adult Anti-Inflammatory Agents Anti-inflammatory Antigens Autoimmune Diseases Birth Bone Marrow Cell Count Cell Maturation Cell Ontogeny Cell physiology ChIP-seq Chromatin Structure Clinical effectiveness Code Complementary DNA Contact Dermatitis Data Defect Dendritic Cells Development Disease Embryo Embryonic Development Enzymes Epigenetic Process Excision Fetal Liver Gene Expression Genes Goals HDAC3 gene HDAC4 gene Histone Deacetylase Histone Deacetylase Inhibitor Histones Homeostasis Hypersensitivity Immune Immune Tolerance In Vitro Individual Infection Inflammation Knock-out Knockout Mice Langerhans cell Macrophage Colony-Stimulating Factor Receptor Maintenance Malignant Neoplasms Mediating Messenger RNA MicroRNAs Molecular Molecular Profiling Monitor Mus Mutant Strains Mice Myelogenous Myeloid Cells Pathway Analysis Pathway interactions Peripheral Play Procedures Proteins Reporting Role Signal Pathway Skin T cell differentiation Techniques Technology Testing Trichostatin A Ultraviolet Therapy Untranslated RNA Yolk Sac adaptive immunity cDNA Arrays chromatin immunoprecipitation experience in vivo macrophage member migration monocyte mouse model non-histone protein public health relevance skin disorder tumor

项目摘要

DESCRIPTION (provided by applicant): Langerhans cells (LCs), the skin residing dendritic cells (DCs), form a contiguous immune network in skin and are involved in allergy, infection, cancer, and autoimmune disease development. However, the regulatory mechanisms involved in the development and functions of LCs have not been completely elucidated. Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or directly deacetylating non- histone proteins, and represent a key epigenetic regulatory mechanism. HDAC inhibitors (HDI) are shown to have anti-tumor and anti-inflammatory effects in a variety of diseases, in which LCs play an important role. However, the mechanisms underlying the clinical effectiveness of HDI remain largely unknown. We recently reported that the inhibition of Class I/II HDACs by Trichostatin A (TSA) regulates the homeostasis and function of LCs in vitro and in vivo and modulates the non-coding miRNA expressions in LCs, while miRNAs also control LC development and function. Our preliminary data indicate that LCs express all Class I/II HDACs. To evaluate the role of individual HDACs in LC development and function, we generated knockout (KO) mice with selective deletion of HDAC3 (Class I) or HDAC4 (Class II) in epidermal LCs. Interestingly, LC number was significantly reduced in LC-HDAC3KO mice, but unaffected in LC-HDAC4KO mice. Furthermore, LC maturation and function were altered in LC-HDAC3KO mice. Thus, we hypothesize that HDAC3 is a key epigenetic component that controls LC development and function. In Aim 1, we will investigate the roles of HDAC3 in LC development and homeostasis, using LC-HDAC3KO mice for homeostasis after birth and using constitutive Csf1r-specific HDAC3-deletion mice (Csf1r-HDAC3) and inducible Csf1r- specific HDAC3-deletion (Csfr1.Mer-HDAC3) mice for early embryonic LC development; Aim 2, we will investigate the roles of HDAC3 in LC function, using inducible LC- ER.HDAC3KO mice. In Aim 3, we will elucidate the molecular mechanisms and signaling pathways by which HDAC3 regulates LC development and function, by combining cDNA array, miRNA array and ChiP-Seq techniques. The proposed studies will uncover the epigenetic regulatory mechanisms of HDAC3 in LC development and function, and may also elucidate new mechanisms for HDI therapy.

描述（由申请人提供）：朗格汉斯细胞（LC），即皮肤中的树突状细胞（DC），在皮肤中形成连续的免疫网络，并参与过敏、感染、癌症和自身免疫性疾病的发展。 LC 的发育和功能尚未完全阐明。组蛋白脱乙酰酶 (HDAC) 是通过修饰染色质结构来调节基因表达的酶。 HDAC 抑制剂（HDI）通过去除靶组蛋白上的乙酰基或直接使非组蛋白脱乙酰化，被证明在多种疾病中具有抗肿瘤和抗炎作用。然而，HDI 临床有效性的机制仍然很大程度上未知，我们最近报道，曲古抑菌素 A (TSA) 抑制 I/II 类 HDAC 可以调节体内平衡和功能。我们的初步数据表明，LC 表达所有 I/II 类 HDAC，并调节 LC 中的非编码 miRNA 表达。我们生成了表皮 LC 中 HDAC3（I 类）或 HDAC4（II 类）选择性缺失的敲除 (KO) 小鼠，这表明，LC 数量显着减少。 LC-HDAC3KO 小鼠，但在 LC-HDAC4KO 小鼠中不受影响。此外，LC-HDAC3KO 小鼠中的 LC 成熟和功能发生改变，因此，我们一直在关注 HDAC3 是控制 LC 发育和功能的关键表观遗传成分。，我们将研究 HDAC3 在 LC 发育和稳态中的作用，使用 LC-HDAC3KO 小鼠进行出生后的稳态，并使用组成型目标 2，我们将使用诱导型 LC-ER.HDAC3KO 小鼠研究 HDAC3 在 LC 功能中的作用。在目标 3 中，我们将阐明分子机制和信号传导。通过结合cDNA阵列、miRNA阵列和ChiP-Seq技术，本研究将揭示HDAC3在LC发育和功能中的表观遗传调控机制，并可能阐明HDI治疗的新机制。