Role of an Integrator-EGR axis in the regulation of myeloid enhancers (Admin Supp)

项目摘要 髓系细胞的单/巨噬细胞承诺由两个截然不同且基本独立的 发展的步骤。首先，造血干细胞不对称分裂生成一系列 在外周有丝分裂后的单核细胞分化中达到顶峰的谱系受限的祖细胞。第二, 血液循环中的单核细胞是短暂的细胞，可以分化成巨噬细胞，巨噬细胞是 能渗透到大多数组织的特化吞噬细胞。而单核细胞可以介导炎症 和细胞毒性，在某种程度上，巨噬细胞拥有对病原体最广泛的一套防御机制 并能引起强烈的炎症反应。 在这项建议中，我们分析了单核细胞和巨噬细胞发育的分子决定因素 锌指Egr1转录因子在髓系细胞中的表达 发展。Egr1对单核细胞的发育是必不可少的，它结合了一系列关键的增强子，这些增强子 调节单核细胞分化。然而，在巨噬细胞中，Egr1具有额外的抑制功能。 炎症增强剂成分。我们建议解剖Egr1在巨噬细胞中的作用范围和 确定与Egr1合作调节表观基因组的蛋白质伙伴。此外，我们建议 阐明伴随着髓系细胞后期发育的染色体构象变化和 确定它们如何影响巨噬细胞促进炎症的能力。

Project Summary Mono/macrophagic commitment of myeloid cells comprises two distinct and largely independent developmental steps. First, hematopoietic stem cells asymmetrically divide to generate a succession of lineage-restricted progenitors that culminate in differentiation of peripheral, post-mitotic monocytes. Second, blood-circulating monocytes are short-lived cells that can undergo differentiation into macrophages, which are specialized phagocytic cells capable of infiltrating most tissues. While monocytes can mediate inflammation and cell toxicity, to some extent, macrophages boast the widest set of defense mechanisms against pathogens and can elicit a robust inflammatory response. In this proposal, we analyze the molecular determinants of monocytic and macrophagic development by profiling the zinc-finger EGR1 transcription factor that has been previously implicated in myeloid cell development. EGR1 is essential for development of monocytes and binds a set of critical enhancers that regulate monocytic differentiation. In macrophages, however, EGR1 boasts an additional repressor function at inflammatory enhancer elements. We propose to dissect the scope of action of EGR1 in macrophages and identify the protein partners that cooperate with EGR1 to regulate the epigenome. Furthermore, we propose to elucidate the chromosome conformation changes that accompany late-stage development of myeloid cells and determine how they impact a macrophage’s ability of promoting inflammation.