Function of Putative Determinant in Hematopoiesis

造血作用中推定决定因素的功能

• 批准号: 8708829
• 负责人: JAMES J BIEKER
• 金额: $ 49.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708829
• 关键词: Address; Alleles; Anemia; Architecture; Biochemical; Biological Assay; Biological Process; Biology; Cells; Chromatin; Chromatin Structure; Collaborations; Complex; Consultations; Coupled; DNA; DNA Polymerase II; DNA-Protein Interaction; Epigenetic Process; Erythroid; Erythroid Cells; Erythropoiesis; Event; Gene Activation; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Globin; Hematology; Hematopoiesis; Histone H3; Histone H3.3; Investigation; Lead; Letters; Link; Maps; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Nuclear; Output; Pattern; Phosphoric Monoester Hydrolases; Play; Point Mutation; Post-Translational Protein Processing; Process; Property; Protein Binding; Protein Deficiency; Proteins; Protocols documentation; RNA; Reagent; Regulation; Regulator Genes; Role; Structural Models; Structure; System; TAF9 gene; Time; Transactivation; Transcript; Transcription Initiation; Transcriptional Regulation; base; design; embryonic stem cell; erythroid Kruppel-like factor; human disease; in vivo; innovation; novel; programs; promoter; protein complex; research study; three dimensional structure; transcription factor

DESCRIPTION (provided by applicant): Cell-restricted transcriptional modulators play critical roles in the process of selective gene regulation during hematopoiesis. We have been investigating the molecular and biological function of Erythroid Kr¿ppel-like Factor (EKLF; KLF1). EKLF is a cell-restricted transcription factor that is essential for the erythroid program. Analysis of EKLF target gene regulation has revealed distinct transactivation mechanisms, and its protein interaction partners suggest additional unexplored roles in transcript control. The experiments of Aim 1 are directed at exploring the parameters of EKLF interactions with proteins and promoter DNA essential for these regulatory steps that lead to successful transcription. Analysis of EKLF's role in establishing an open chromatin structure, coupled with its interaction with histone H3 and the selective increase of H3.3 at the ¿-globin promoter, suggest these observations are linked. As a result, the experiments of Aim 2 will address EKLF's role in coordinating histone H3.3 incorporation into chromatin. Analysis of the anemia in the heterozygous Nan mutant mouse has exposed an unexplained mechanism of gene-selective EKLF activation that leads to unique protein deficiency. The experiments of Aim 3 are designed to illuminate the molecular mechanism of the genetic distortion that results from the presence of Nan-EKLF in the erythroid cell. These studies will be aided by the use of in vivo assays, EKLF rescue systems, and primary or minimally manipulated cells. Elucidating EKLF's role in regulatory phenomena will continue to illuminate novel aspects of erythroid biology and the essential mechanisms by which a cell-restricted transcription factor can exert varied yet highly controlled influences on genetic expression and epigenetics.

描述（由适用提供）：细胞限制的转录调节剂在造血过程中选择性基因调节过程中起关键作用。我们一直在研究红斑kr kr样的分子和生物学功能（EKLF; KLF1）。 EKLF是细胞限制的转录因子，对红细胞程序必不可少。 EKLF靶基因调节的分析揭示了不同的反式激活机制，其蛋白质相互作用伙伴表明在转录本控制中的其他意外作用。 AIM 1的实验旨在探索EKLF相互作用与蛋白质和启动子DNA的参数，而这些调节步骤必不可少的启动子DNA。分析EKLF在建立开放染色质结构中的作用，再加上与组蛋白H3的相互作用以及在»globin启动子处的H3.3的选择性增加，这表明这些观察结果已链接。结果，AIM 2的实验将解决EKLF在染色质中掺入的EKLF在协调组蛋白H3.3中的作用。杂合NAN突变小鼠中贫血的分析暴露了一种意外的基因选择性EKLF激活机制，从而导致独特的蛋白质缺乏。 AIM 3的实验旨在阐明遗传失真的分子机制，这是由于红细胞细胞中NAN-EKLF的存在而引起的。这些研究将通过使用体内测定，EKLF救援系统以及原代或微小操纵细胞来帮助这些研究。阐明EKLF在调节现象中的作用将继续阐明红斑生物学的新方面，以及细胞限制的转录因子可以发挥不同但高度控制对遗传表达和表观遗传学的影响的基本机制。