Runx1 Binding Sites as Scaffolds That Mediate Chromosome Translocation

Runx1 结合位点作为介导染色体易位的支架

• 批准号: 7126234
• 负责人: Janet L Stein
• 金额: $ 3.94万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126234
• 关键词: Accounting; Acute; Acute Myelocytic Leukemia; Address; Architecture; Area; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biological Models; Bone Tissue; CCAAT-Enhancer-Binding Proteins; Calvaria; Cell Nucleus; Cells; Characteristics; Chile; Chromatin; Chromatin Structure; Chromosomal translocation; Chromosome Territory; Chromosomes; Chromosomes, Human, Pair 21; Collaborations; Complex; Condition; Coupled; Coupling; Cues; DNA; DNA Double Strand Break; DNA Sequence; DNA-Binding Proteins; Data; Detection; Development; Disease; Elements; Employee Strikes; Event; Experimental Designs; Fetal Development; Fluorescence Microscopy; Frequencies; Future; Gene Activation; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genomics; Goals; Grant; Hematopoietic; Histone H4; Histones; Hormone Responsive; Human Characteristics; Hypersensitivity; In Situ; Introns; Laboratories; Lead; Life; Link; Location; Mediating; Methods; Modification; Molecular; Molecular Conformation; Molecular Structure; Monitor; Mus; Mutation; Nuclear; Nuclear Envelope; Nuclear Matrix; Nuclear Structure; Nucleosomes; Osteoblasts; Osteocalcin; Osteogenesis; Pattern; Physiological; Positioning Attribute; Post-Translational Protein Processing; Predisposing Factor; Predisposition; Process; Protein Dynamics; Proteins; Psyche structure; RUNX1 gene; Recombinants; Recruitment Activity; Regulatory Element; Research; Role; Skeletal Development; Skeletal system; Staging; Structure; Susceptibility Gene; Testing; Trans-Activators; Transcriptional Activation; Transcriptional Regulation; Transgenes; United States National Institutes of Health; Vitamin D; Work; base; bone; chromatin remodeling; chronic leukemia; cofactor; genetic regulatory protein; in vivo; insight; mutant; novel; nuclease; parent grant; prevent; programs; promoter; research study; response; scaffold; steroid hormone; t(8; 21)(q22; q22); tool; transcription factor

DESCRIPTION (provided by applicant): A striking characteristic of the human acute and chronic leukemias is the finding that they are the result of nonrandom, somatically acquired chromosomal translocations. The long-term goal of our research is to determine if there is a common mechanism involved in the generation of chromosomal translocations. As a biological model, we are using the RUNX1 gene, which encodes an important hematopoietic transcription factor and is the most frequent target of chromosomal translocations in acute myeloid leukemia (AMI). The RUNX1 gene is located on chromosome 21, and interestingly, for both the (8; 21) and (16; 21) AML-related translocations, all the genomic breakpoints are found in intron 5. Therefore, a key question is what are the factors that predispose the RUNX1 gene to be involved in chromosomal translocations? Our working hypothesis is that the chromatin structure present at the breakpoint regions is determinant for the t(8;21) translocation. Moreover, we hypothesize that the sub-nuclear localization of a gene may be determinant both of the gene susceptibility to dsDNA breaks and in the selection of the partner gene when a translocation is generated. A detailed comparison between the structural characteristics of chromatin and the nuclear positioning of the RUNX1, ETO and the recombinant AML/ETO locus will allow us to identify the presence of common features that may account for the increased accessibility observed at the breakpoint regions. The proposed experiments based on our preliminary data will combine the expertise of the collaborating laboratories to investigate the cis and trans acting factors that can be determinants of the RUNX1 locus recombination frequency. The focus of the parent grant is the interrelationship between chromatin organization, nuclear compartmentalization of Runx factors, and gene expression. In this FIRCA proposal, we extend the scope of these studies to address the relationship between Runx regulatory factors, nuclear localization, and susceptibility to chromosomal translocations. This research will be done primarily in Chile at the Universidad de Concepcion in collaboration with Soraya Gutierrez as an extension of NIH grant 5P01 AR48818, projects.

描述（由申请人提供）：人类急性和慢性白血病的一个显着特征是发现它们是非随机的、体细胞获得性染色体易位的结果。我们研究的长期目标是确定染色体易位的产生是否存在共同机制。作为生物学模型，我们使用 RUNX1 基因，该基因编码重要的造血转录因子，并且是急性髓系白血病 (AMI) 染色体易位最常见的靶标。 RUNX1基因位于21号染色体上，有趣的是，对于（8；21）和（16；21）AML相关易位，所有基因组断点都在内含子5中发现。因此，一个关键问题是哪些因素导致RUNX1基因容易参与染色体易位？我们的工作假设是断点区域的染色质结构是 t(8;21) 易位的决定因素。此外，我们假设基因的亚核定位可能决定基因对 dsDNA 断裂的敏感性以及易位产生时伴侣基因的选择。染色质结构特征与 RUNX1、ETO 和重组 AML/ETO 基因座的核定位之间的详细比较将使我们能够确定共同特征的存在，这些特征可能解释在断点区域观察到的可及性增加。基于我们初步数据的拟议实验将结合合作实验室的专业知识，研究可能成为 RUNX1 位点重组频率决定因素的顺式和反式作用因素。父母资助的重点是染色质组织、Runx 因子的核区划和基因表达之间的相互关系。在此 FIRCA 提案中，我们扩展了这些研究的范围，以解决 Runx 调控因子、核定位和染色体易位易感性之间的关系。这项研究将主要在智利康塞普西翁大学与 Soraya Gutierrez 合作进行，作为 NIH 拨款 5P01 AR48818 项目的延伸。