Chromatin architecture as a regulator of dendritic cell function

项目摘要 树突状细胞（Dendritic cells，DC）是一种免疫哨兵细胞，可被先天性刺激激活，协调机体的适应性免疫反应。 免疫反应。常规DC（cDC）有效地呈递和交叉呈递抗原以引发T细胞活化。 浆细胞样DC（pDC）快速产生I型干扰素（IFN-α/β，IFN-I）和其他干扰素。 细胞因子对病原体来源的核酸的应答。最近的研究揭示了一个复杂的拓扑结构 将基因组组织成拓扑相关结构域（TADs），这些结构域是通过粘连蛋白建立的， 介导的环挤出，并通过转录因子CTCF的结合位点划界。CTCF/粘附素- 介导的染色质结构被认为控制细胞类型特异性基因表达程序，从而 促进细胞分化和功能。然而，树突状细胞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描述 DC中的染色质结构，并阐明DC功能的染色质水平控制。在目标1中，我们 检查CTCF/粘附素介导的调节在DC亚群分化中的作用。在目标2中，我们将 分析粘附素在DC功能中的作用，包括细胞因子应答和抗原呈递。在目标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IFN-γ中的作用。 DC中的干扰素产生。总的来说，这些结果将提供新的见解的作用， DC分化和功能调节中的染色体组织机制。

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.