Control of the Erythroid Terminal Differentiation Decision

红细胞终末分化决策的控制

• 批准号: 8344044
• 负责人: ARTHUR I SKOULTCHI
• 金额: $ 36.32万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344044
• 关键词: ATP phosphohydrolase; Acute; Address; Anemia; Binding; Blood; Cell Count; Cell Cycle; Cell Cycle Progression; Cell Differentiation process; Cell Proliferation; Cell Proliferation Regulation; Cells; Chronic; Complex; Cyclin D1; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Defect; Development; Down-Regulation; Embryo; Enzymes; Equilibrium; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Family; Fetal Liver; G1 Phase; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic System; Intervention; Knockout Mice; Knowledge; Lead; Link; Maintenance; Mediating; Output; Phosphotransferases; Play; Process; Production; Proliferating; Property; Recruitment Activity; Regulation; Regulatory Element; Repression; Role; S Phase; SMARCA5 gene; SPI1 gene; Series; Source; Stress; System; Work; chromatin remodeling; erythroid differentiation; human GATA1 protein; insight; novel strategies; progenitor; programs; promoter; proto-oncogene protein Spi-1; research study; self-renewal; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate the factors and mechanisms that control the decision of early erythroid progenitors to undertake terminal differentiation. Much evidence suggests that a crucial aspect of differentiation decisions is a requirement for coordination with the cell proliferation program. However, our current knowledge about the connections between the cell proliferation and differentiation programs is very limited. Work from our lab and others has identified the Ets - family transcription factor PU.1 as a key regulator of the terminal differentiation decision in early erythroid progenitors. And yet, the factors that control PU.1 expression and activity in these early erythroid progenitors and the mechanisms that link the differentiation decision to the cell cycle are not known. Recently, we identified two types of factors that have a very strong potential for connecting PU.1 and the terminal differentiation decision to the cell cycle. One factor is CDK6, which we discovered inhibits erythroid differentiation, like PU.1. We also showed that: 1) CDK6 is the active G1 phase D-cyclin kinase in erythroid progenitors; 2) PU.1 controls transcription of the CDK6 gene; 3) CDK6 phosphorylates PU.1. The other factors are E2F2 and E2F4, transcriptions factors that play major roles in G1 to S phase cell cycle progression. We found that E2F2 and E2F4 occupy the promoter and upstream regulatory element (URE) of the PU.1 gene in erythroid progenitors. They also bind very close to PU.1 at many other PU.1 target genes in these cells. In Aims 1 and 2, we propose a series of experiments to determine how CDK6 and E2F2 and E2F4 influence PU.1 expression and activity and how they collaborate with PU.1 in the erythroid terminal differentiation decision. We also propose to investigate roles for CDK6 and E2F2 in stress erythropoiesis and in ex vivo self-renewal of erythroid precursors. Work from our lab and others showed that one of the principal mechanisms used by PU.1 to regulate the erythroid differentiation decision is repression of erythroid-specific gene expression Recently, we discovered that PU.1 forms a complex with the chromatin remodeling ATPase SNF2H and the maintenance DNA methyltransferase DNMT1; two enzymes that we hypothesize help PU.1 to repress erythroid gene expression. In Aim 3, we propose studies to elucidate the role of SNF2H and DNMT1 in PU.1-mediated repression of erythroid-specific genes and inhibition of erythroid terminal differentiation. The successful completion of the proposed studies will lead to new insights into the mechanisms connecting the proliferation and differentiation programs in hematopoietic cells and a much deeper understanding of how the hematopoietic system regulates red blood cell production, including during ontogeny and in stress conditions. The proposed work will also provide important information enabling the development of new approaches to managing defects in red blood cell production that occur in chronic and acute anemia. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to understand the factors and mechanisms that regulate the decision of red blood cell precursors to undertake terminal differentiation into mature red blood cells. The proposed studies are expected to provide important new information about how the blood system normally produces the proper number of red blood cells and how it responds to the need to produce more red cells in stress conditions. Some of the proposed work will involve identification of factors that are required for expansion of red blood cell precursors ex vivo, an approach that could provide a source of red blood cells for transfusion therapy. The successful completion of this work will enable the development of new approaches to managing defects in red blood cell production that occur in chronic and acute anemia due to a variety of causes.

项目描述（由申请人提供）：本项目的总体目标是阐明控制早期红系祖细胞进行终末分化决策的因素和机制。许多证据表明，差异化决策的一个关键方面