Chromatin architecture as a regulator of dendritic cell function

染色质结构作为树突状细胞功能的调节剂

基本信息

批准号：
10594026
负责人：
Boris Reizis
金额：
$ 54.74万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-17 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594026
关键词：
3-Dimensional ATAC-seq Antigen Presentation Architecture Autoimmune Diseases Binding Binding Sites CSPG6 gene Cell Differentiation process Cell physiology Cells Cellular biology Chromatin Chromatin Loop Chromatin Modeling Chromosome Structures Cross Presentation Data Dendritic Cells Development Disease Enhancers Epigenetic Process Future Gene Expression Genes Genetic Transcription Genome Goals Hi-C Immune Immune response Impairment In Vitro Infection Control Interferon Type I Interferon alpha Interferons Interleukin-12 Malignant Neoplasms Mediating Mediator Modeling Molecular Nucleic Acids Production Regulation Role Sentinel Site Specific qualifier value Stimulus T cell response T-Lymphocyte TCF7L2 gene Testing Therapeutic Transcriptional Regulation adaptive immune response cell type chromosome conformation capture cohesin cytokine genome-wide in vitro Model in vivo insight mammalian genome migration novel pathogen programs promoter protein complex recruit response stem cells transcription factor transcriptome transcriptome sequencing

项目摘要

PROJECT ABSTRACT Dendritic cells (DCs) are immune sentinel cells that can be activated by innate stimuli to orchestrate adaptive immune responses. Conventional DCs (cDCs) efficiently present and cross-present antigens to prime T cell responses, whereas plasmacytoid DCs (pDCs) rapidly produce type I interferon (IFN-α/β, IFN-I) and other cytokines in response to pathogen-derived nucleic acids. Recent studies revealed an intricate topological organization of the genome into topologically associated domains (TADs) established through cohesin- mediated loop extrusion and demarcated by binding sites of transcription factor CTCF. CTCF/cohesin- mediated chromatin architecture is thought to control cell type-specific gene expression programs, thereby facilitating cell differentiation and function. However, the topological chromatin landscapes of DCs and their role in DC differentiation and function are poorly understood. The overall goal of the project is to characterize the chromatin architecture in DCs and elucidate the chromatin-level control of DC function. In Aim 1, we will examine the role of CTCF/cohesin-mediated regulation in the differentiation of DC subsets. In Aim 2, we will analyze the role of cohesin in DC function, including cytokine responses and antigen presentation. In Aim 3, we will analyze the architecture of the locus encoding IFN-I genes, and the role of chromatin in the control of interferon production in DCs. Collectively, these results would provide novel insights into the role and mechanism of chromosomal organization in the regulation of DC differentiation and function.

项目摘要树突状细胞（DC）是免疫素细胞，可以通过先天刺激激活以编排适应性的细胞免疫反应。常规DC（CDC）有效地存在和交叉抗原与原始T细胞响应，而浆细胞类动物DC（PDC）迅速产生I型干扰素（IFN-α/β，IFN-I）和其他响应病原体衍生的核酸的细胞因子。最近的研究揭示了一个复杂的拓扑将基因组组织成拓扑相关的领域（TAD）介导的循环扩展，并通过转录因子CTCF的结合位点划分。 CTCF/粘着素 - 介导的染色质结构被认为控制特定于细胞类型的基因表达程序，从而控制了促进细胞分化和功能。但是，DC的拓扑染色质景观及其在DC分化和功能中的作用知之甚少。该项目的总体目标是表征 DC中的染色质体系结构并阐明了直流功能的染色质级控制。在AIM 1中，我们将检查CTCF/粘蛋白介导的调节在DC子集分化中的作用。在AIM 2中，我们将分析粘着蛋白在直流功能中的作用，包括细胞因子反应和抗原表现。在AIM 3中，我们将分析编码IFN-I基因的基因座的结构，以及染色质在控制中的作用干扰素生产DC。总的来说，这些结果将为角色和 DC分化和功能调节中染色体组织的机制。