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

Integrator-EGR 轴在骨髓增强子调节中的作用（管理补充）

基本信息

批准号：
10007301
负责人：
Alessandro Gardini
金额：
$ 10.1万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-08 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007301
关键词：
3-Dimensional Acetylation Affect Architecture Binding Biochemistry Biological Process Blood CD34 gene CSF1R gene Cells ChIP-seq Chromatin Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Defense Mechanisms Development Elements Enhancers Gatekeeping Genes Genetic Enhancer Element Genome Goals Hematopoietic stem cells Human Inflammation Inflammatory Inflammatory Response Literature Macrophage Colony-Stimulating Factor Maps Mediating Microbe Mitotic Molecular Molecular Conformation Myelogenous Myeloid Cells Myelopoiesis NuRD complex Organ Peripheral Phagocytes Physiology Proteins RNA RNA analysis Regulation Regulatory Element Repression Repressor Proteins Role Shapes Site Testing Time Tissues Toxic effect Transcription Process Umbilical Cord Blood Zinc Fingers base cell transformation epigenome genetic corepressor genome analysis genome-wide human tissue macrophage monocyte myeloid cell development novel parent grant pathogen peripheral blood progenitor protein complex recruit stem cells transcription factor

项目摘要

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.

项目摘要髓样细胞的单/巨噬型承诺包括两个独特的独立性发展步骤。首先，造血干细胞不对称地分裂以产生成功谱系限制的祖细胞，在分化的周围有序后单核细胞分化。第二，血循环单核细胞是短暂的细胞，可以将其分化为巨噬细胞，能够渗透大多数组织的专门吞噬细胞。而单核细胞可以介导注射在某种程度上，巨噬细胞拥有针对病原体的最广泛的防御机制，并具有细胞毒性并可以引起强大的炎症反应。在此提案中，我们通过通过该提案分析了通过分析先前与髓样细胞有关的锌指EGR1转录因子发展。 EGR1对于开发单核细胞至关重要，并结合一组关键增强剂调节单核细胞分化。但是，在巨噬细胞中，Egr1在炎症增强子元素。我们建议剖析巨噬细胞中eGR1的作用范围确定与EGR1合作以调节表观基因组的蛋白质伴侣。此外，我们建议阐明染色体会议的变化，以适应髓样细胞的晚期发展和确定它们如何影响巨噬细胞促进炎症的能力。