Regulators of the Erythroid Terminal Differentiation Decision and their Connection to the Cell Cycle

红细胞终末分化决定的调节因子及其与细胞周期的联系

• 批准号: 9318530
• 负责人: Michael Alton Willcockson
• 金额: $ 4.9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318530
• 关键词: Alpha Cell; Anemia; B-Lymphocytes; Binding; Biological Assay; Cell Cycle; Cell Cycle Progression; Cells; ChIP-seq; Clinical; Complex; Computer Analysis; Computing Methodologies; DNA Binding; DNA-Binding Proteins; Data; Data Set; Defect; Deoxyribonucleases; Distal; Down-Regulation; Ectopic Expression; Enhancers; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exhibits; Family; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Goals; Hematopoietic; Hypersensitivity; Knock-out; Knockout Mice; Measures; Molecular; Molecular Models; Nucleic Acid Regulatory Sequences; Outcome Study; Output; Phenotype; Publishing; Refractory anemias; Regulation; Regulatory Element; Reporter; Role; S Phase; Site; T-Lymphocyte; Transcription Factor AP-1; Transfection; Work; cell type; combinatorial; genome-wide; insight; macrophage; molecular modeling; progenitor; programs; public health relevance; self-renewal; transcription factor

 DESCRIPTION (provided by applicant): BFUe, the most primitive committed erythroid progenitors, are capable of extensive proliferation. BFUe differentiate into CFUe, cells with very restricted proliferative potential. Pu.1 is a hematopoietic, master regulatory ETS transcription factor (TF) that is required for BFUe self-renewal. PU.1 inhibits BFUe differentiation. Down regulation of PU.1 occurs and is required for BFUe to differentiate into CFUe. Despite Pu.1's central role in regulating the terminal differentiation decision, the molecular mechanism controlling Pu.1's expression and down-regulation are not known. We propose to identify the cis-regulatory elements that control Pu.1 expression in BFUe and it's down regulation as these progenitors enter terminal differentiation. Using computational analysis of gene expression, ChIP Seq and other types of genome-wide data sets, we have identified several DNA binding proteins as candidates for controlling Pu.1 expression in BFUe, including SATB1, E2F4, Runx and Jun. The analysis also suggests that some of these factors, Runx and Jun, collaborate with Pu.1 to regulate a large set of genes that promote proliferation of BFUe and antagonize their terminal differentiation. We propose to determine whether these factors regulate Pu.1 expression. We also propose to determine whether they work in concert with Pu.1 to control a set of important gene targets in erythroid cells. The successful completion of this work will provide essential insights into the transcriptional networks that regulate red blood cell output.

 描述（由申请人提供）：BFUe是最原始的定向红系祖细胞，能够广泛增殖。BFUe分化成CFUe，具有非常有限的增殖潜力的细胞。Pu.1是BFUe自我更新所需的造血、主调节ETS转录因子（TF）。PU.1抑制BFUe分化。PU.1发生下调，并且是BFUe分化为CFUe所必需的。尽管Pu.1在调节终末分化决定中的中心作用，但控制Pu.1表达和下调的分子机制尚不清楚。我们建议确定控制Pu.1在BFUe中表达的顺式调控元件，以及随着这些祖细胞进入终末分化而下调。使用基因表达的计算分析，ChIP Seq和其他类型的全基因组数据集，我们已经确定了几种DNA结合蛋白作为控制BFUe中Pu.1表达的候选物，包括SATB 1，E2F4，Runx和Jun。分析还表明，其中一些因素，Runx和Jun，与Pu.1合作调节促进BFUe增殖并拮抗其终末分化的大量基因。我们建议确定这些因素是否调节Pu.1表达。我们还建议确定它们是否与Pu.1协同工作，以控制红系细胞中的一组重要基因靶点。这项工作的成功完成将为调节红细胞输出的转录网络提供重要的见解。