Transcriptional Control of Hemoglobin Synthesis and Erythrocyte Development

血红蛋白合成和红细胞发育的转录控制

• 批准号: 10452635
• 负责人: Emery H Bresnick
• 金额: $ 47.84万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452635
• 关键词: Abnormal Red Blood Cell; Adenosine; Amino Acids; Apoptosis; Apoptotic; BACH1 gene; Biological; Biology; Blood Vessels; Carrier Proteins; Cells; Ceramides; Chromatin; Complement; Complex; Congenital Anemia; Cultured Cells; Defect; Development; Dimensions; Disease; Down-Regulation; Elements; Enhancers; Ensure; Enzymes; Epigenetic Process; Erythroblasts; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Feedback; Foundations; GATA1 gene; Gene Expression; Genes; Genetic Engineering; Genetic Transcription; Genome; Globin; Grant; Hematology; Hematopoiesis; Heme; Hemoglobin; Human; Impairment; Knowledge; Lead; Link; Lipids; Logic; Mediating; Metals; Modeling; Molecular and Cellular Biology; Mus; Mutate; Natural regeneration; Pathologic; Pathology; Pathway interactions; Process; Proliferating; Pyruvate Kinase; Red Blood Cell Count; Regulation; Resistance; SAM Domain; Sickle Cell Anemia; Signal Transduction; Signaling Molecule; Sphingolipids; System; Technology; Tertiary Protein Structure; Testing; Therapeutic Agents; Transcriptional Regulation; Work; adenosine transporter; base; beta Globin; blood product; bone marrow failure syndrome; ceramide 1-phosphate; cohort; dihydroceramide desaturase; erythroid differentiation; genome editing; genome-wide; heme biosynthesis; innovation; insight; lipidomics; loss of function; migration; multiple omics; prevent; progenitor; pyruvate kinase deficiency; small molecule; solute; sphingosine 1-phosphate; stem; stem cells; transcription factor; zinc-binding protein

PROJECT SUMMARY Hemoglobin synthesis and erythrocyte development are often studied independently, yet their mechanisms are inextricably linked. Differentiation defects yield immature precursors, and impaired hemoglobin synthesis causes ineffective erythropoiesis. A common thread of these mechanisms is GATA transcription factor involvement. Many questions remain regarding how GATA factor networks instruct progenitors to generate vast numbers of erythrocytes, which broadly informs molecular/cellular biology and hematology. We discovered: 1) locus-specific coregulator utilization by GATA1 to control differentiation; 2) GATA factor/regeneration-activated enhancer confers expression of an unstudied sterile alpha motif domain protein that controls erythrocyte regeneration; 3) GATA factor-regulated zinc transporter switch governs differentiation; 4) mechanism of heme targeting chromatin genome-wide; 5) GATA factor-regulated solute carrier protein (SLC) cohort transports diverse small molecules to control erythropoiesis. Our multi-omic work supports the aims to analyze how GATA factors establish small molecule ensembles that target the genome and regulate the GATA factor to ensure differentiation. Aim 1 will dissect a multi-component mechanism by which GATA1 and heme control genome function and erythrocyte development. GATA1 activates genes mediating heme biosynthesis, heme facilitates or restricts GATA1 function and heme downregulates GATA1. Heme regulates transcription by downregulating the repressor Bach1, and we discovered a Bach1-independent heme-regulated mechanism. We hypothesize that Bach1-dependent and -independent mechanisms establish critical erythroid functions, and these mechanisms provide translational opportunities. Using all heme target genes and a gene-specific approach, we will establish the mechanisms. Aim 2 will elucidate a GATA factor-dependent small molecule transporter axis that regulates erythroid differentiation. We hypothesize that diverse small molecules function in GATA factor mechanisms and discovering GATA factor-regulated solute carrier (Slc) transporters will unveil new dimensions to these mechanisms. We defined a GATA1/2-regulated Slc cohort that transports diverse small molecules. We prioritized a subset with GATA factor-occupied predicted enhancers and will elucidate mechanisms that link GATA factors with small molecule ensembles and differentiation. Aim 3 will test models for how GATA1 instigates a sphingolipid-dependent regulatory network. GATA1-regulated Slcs included sphingolipid transporters. Lipidomics revealed GATA1-induced sphingolipid remodeling. Ceramide synthase inhibition blocks GATA1-mediated GATA2 downregulation, β-globin induction and erythroid maturation. Sphingolipid signaling controls apoptosis, proliferation and migration, high S1P is deleterious in sickle cell disease, and human ceramide deficiency involves disrupted erythropoiesis. We hypothesize that sphingolipidome regulation by GATA1 is vital in biology and pathology. We will develop basic and translational insights into GATA factor mechanisms governing small molecules that control GATA factors, globin synthesis and differentiation.

项目概要 血红蛋白合成和红细胞发育通常是独立研究的，但它们的机制尚不清楚 有着千丝万缕的联系。分化缺陷产生不成熟的前体，血红蛋白合成受损导致 红细胞生成无效。这些机制的一个共同点是 GATA 转录因子的参与。 关于 GATA 因子网络如何指导祖细胞产生大量细胞，仍然存在许多问题。 红细胞，广泛涉及分子/细胞生物学和血液学。我们发现：1）位点特异性 GATA1 利用核心调节器来控制分化； 2) GATA因子/再生激活增强子 赋予未经研究的无菌α基序结构域蛋白的表达，该蛋白控制红细胞再生； 3） GATA 因子调节的锌转运蛋白开关控制分化； 4）血红素靶向染色质的机制 全基因组； 5）GATA因子调节的溶质载体蛋白（SLC）群运输不同的小分子 来控制红细胞生成。我们的多组学工作支持分析 GATA 因素如何建立小 靶向基因组并调节 GATA 因子以确保分化的分子集合体。目标1将 剖析 GATA1 和血红素控制基因组功能的多组分机制 红细胞发育。 GATA1激活介导血红素生物合成的基因，血红素促进或限制 GATA1 功能和血红素下调 GATA1。血红素通过下调 阻遏物 Bach1，我们发现了一种独立于 Bach1 的血红素调节机制。我们假设 Bach1 依赖和独立机制建立了关键的红细胞功能，这些机制 提供翻译机会。使用所有血红素目标基因和基因特异性方法，我们将建立 的机制。目标 2 将阐明 GATA 因子依赖性小分子转运轴 调节红细胞分化。我们假设不同的小分子在 GATA 因子中发挥作用 机制和发现 GATA 因子调节溶质载体 (Slc) 转运蛋白将揭示新维度 到这些机制。我们定义了一个受 GATA1/2 调节的 Slc 队列，可运输不同的小分子。我们 优先考虑具有 GATA 因子占据的预测增强子的子集，并将阐明链接的机制 GATA 因子具有小分子整体和分化。 Aim 3 将测试模型以了解 GATA1 启动鞘脂依赖性调节网络。 GATA1 调节的 Slc 包含鞘脂 运输者。脂质组学揭示了 GATA1 诱导的鞘脂重塑。神经酰胺合酶抑制块 GATA1 介导的 GATA2 下调、β-珠蛋白诱导和红细胞成熟。鞘脂信号传导 控制细胞凋亡、增殖和迁移，高 S1P 对镰状细胞病有害，而人类 神经酰胺缺乏涉及红细胞生成破坏。我们假设鞘脂组的调节 GATA1 在生物学和病理学中至关重要。我们将开发对 GATA 因素的基本和转化见解 控制 GATA 因子、珠蛋白合成和分化的小分子的机制。