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

基本信息

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
项目类别：
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

项目摘要

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引人注目的特征是发现它们是非随机，体外获得的染色体易位的结果。我们研究的长期目标是确定染色体易位产生是否存在共同的机制。作为一种生物学模型，我们正在使用Runx1基因，该基因编码了重要的造血转录因子，并且是急性髓样白血病（AMI）中染色体易位的最常见靶标。 Runx1基因位于21染色体上，有趣的是，对于（8; 21）和（16; 21）与AML相关的易位，所有基因组断点均在内含子5中发现。因此，一个关键问题是易易于参与染色体易位的Runx1基因的因素是什么？我们的工作假设是，在断点区域存在的染色质结构是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是dsDNA断裂的基因敏感性以及当产生易位时选择伴侣基因的基因敏感性。染色质的结构特征与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可能占断裂点区域可访问性的共同特征的存在。提出的基于我们初步数据的实验将结合合作实验室的专业知识，以研究可以确定Runx1基因座重组频率的CIS和反式作用因素。父授予的重点是染色质组织，RUNX因子的核分区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调节因素，核定位和对染色体易位的易感性之间的关系。这项研究将主要在智利康塞佩西翁大学与索拉亚·古铁雷斯（Soraya Gutierrez）合作，作为NIH Grant 5p01 AR48818项目的扩展。