Chromatin Structure and Dynamics

染色质结构和动力学

• 批准号: 7884847
• 负责人: James T. Kadonaga
• 金额: $ 17.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884847
• 关键词: ATP phosphohydrolase; Address; Affinity; Alleles; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Process; Cell Nucleus; Cells; Cessation of life; Chromatin; Chromatin Modeling; Chromatin Structure; Chromosomes; Classification; Complex; DNA; Dysplasia; Enzymes; Event; Family; Grant; HMGN Proteins; HMGN2 gene; Histones; Human; Human Genome; ISWI; In Vitro; Knowledge; Laboratories; Lead; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Biology; Molecular Chaperones; Molecular Motors; Motor; Mutation; Non-Histone Chromosomal Proteins; Nucleosomes; Pathway interactions; Process; Property; Protein Binding; Proteins; Research; Research Design; Research Project Grants; Source; Techniques; Testing; Time; Transcriptional Activation; base; early childhood; experience; genome-wide; human disease; in vivo; insight; motor control; mutant; novel; research study

The long-term objective of this project is to understand the function of chromatin in the nucleus, with a particular emphasis on the molecular biology of chromatin structure and dynamics. Specific Aim 1 investigates chromatin assembly, a fundamental biological process that is required for the replication and maintenance of our chromosomes. Two key enzymes that .mediate chromatin assembly are the ACF and CHD1 motor proteins. The proposed studies are designed to examine directly the mechanisms by which nucleosomes are assembled by ACF and CHD1. Specific Aim 2 examines the function of human HARP, a protein that is closely related to the ATPase subunits of chromatin assembly and remodeling factors, which include ACF and CHD1. Mutations in HARP are responsible for Schimke immuno-osseous dysplasia (SIOD), which typically leads to death in early childhood. The proposed experiments are a systematic analysis of the function of HARP in vivo and in vitro, and will provide new knowledge that should advance the potential treatment of SIOD. Specific Aim 3 addresses the function of the four human HMGN proteins, which are abundant nonhistone chromosomal proteins that bind specifically to nucleosomes at two high-affinity binding sites. The proposed studies will identify and characterize the interactions of each of the HMGN proteins over 30 Mb of the human genome, and investigate the molecular basis for the phenomena observed in vivo. Given their abundance and nucleosome-binding activity, the HMGN proteins are likely to have a significant impact upon chromatin structure and activity. These studies should lead to a better understanding of chromatin, and should therefore provide new insights into the molecular basis and potential treatment of human diseases, such as many forms of cancer, that involve abnormalities in chromatin structure and DNA-directed processes in chromatin. Importantly, the analysis of HARP should reveal key aspects of the molecular events that lead to SIOD.

该项目的长期目标是了解染色质在细胞核中的功能， 特别强调染色质结构和动力学的分子生物学。具体目标1 调查染色质组装，这是复制所需的基本生物学过程 维护我们的染色体。介质染色质组装的两个关键酶是ACF，并且 CHD1运动蛋白。拟议的研究旨在直接检查 核小体由ACF和CHD1组装。特定目标2检查了人竖琴的功能，一个 与染色质组装和重塑因子的ATPase亚基密切相关的蛋白质，这些因子 包括ACF和CHD1。竖琴中的突变导致Schimke免疫 - 骨不典型增生 （SIOD），通常在幼儿时导致死亡。提出的实验是系统的 分析竖琴在体内和体外的功能，并将提供应提高的新知识 SIOD的潜在处理。特定目标3解决了四种人类HMGN蛋白的功能， 是丰富的非组蛋白染色体蛋白，在两个处专门与核小体结合 高亲和力结合位点。拟议的研究将确定并表征每个研究的相互作用 HMGN蛋白超过30 MB的人类基因组，并研究了现象的分子基础 在体内观察到。鉴于它们的丰度和核小体结合活性，HMGN蛋白可能很可能 对染色质结构和活性有重大影响。 这些研究应导致对染色质的更好理解，因此应提供新的见解 进入分子基础和人类疾病的潜在治疗，例如许多形式的癌症 在染色质中涉及染色质结构和DNA指导过程的异常。重要的是， 竖琴的分析应揭示导致SIOD的分子事件的关键方面。