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）

• 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
• 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

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.

项目总结