Linking Maintenance of Chromosome Structure to Transcriptional Regulation

将染色体结构的维持与转录调控联系起来

• 批准号: 8316505
• 负责人: Jill Dowen
• 金额: $ 5.22万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316505
• 关键词: Area; Cell Maintenance; Cells; ChIP-seq; Chromatin; Chromatin Loop; Chromosome Structures; Chromosomes; DNA Packaging; Data; Defect; Deformity; Development; Enhancers; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genomics; Lead; Link; Maintenance; Malignant Neoplasms; Maps; Mediating; Methodology; Mitosis; Modeling; Molecular; Organism; Pathway interactions; Pattern; Play; Process; Proteins; Research; Role; Site; Stem cells; Structure; Syndrome; Technology; Transcriptional Regulation; base; cell type; chromatin immunoprecipitation; cohesin; condensin; design; embryonic stem cell; genome-wide; interest; member; programs; promoter; protein complex; research study; self-renewal; tumor progression

DESCRIPTION (provided by applicant): The precise regulation of gene expression in the cell is an important task only accomplished by the coordination of multiple molecular pathways. One of these pathways involves the regulation of transcription by chromosome structural components. Aberrant control of chromosome structure is associated with a variety of developmental syndromes, deformities, and the progression of tumors due to the misregulation of genes. Recent evidence has linked chromosome structure to gene expression via the formation of DNA loops that bring enhancers in proximity to promoters during enhancer-loop-mediated transcription. Stem cells represent an ideal cell type to dissect transcriptional regulation due to their unique abilities to differentiate into any cell type of an organism, and alo self-renew. To study the molecular processes regulating transcription of the genome we will employ high-throughput genomic-based technologies and methodologies. The objective of this proposed research is to understand the role of Condensin, a protein complex required for the structural maintenance of chromosomes, in mediating transcription. We will map the distribution of Condensin on the genome and we will identify factors responsible for recruitment and distribution of Condensin. We will examine the pattern of genome-wide occupancy of Condensin with other known members of the transcriptional apparatus and also correlate this pattern with gene expression data. Uncovering the function of chromosome structure in transcription remains a largely unexplored area of research and should be considered essential in fully appreciating the interplay between the various processes that influence gene expression programs in the cell. PUBLIC HEALTH RELEVANCE: The packaging of DNA into chromatin is a highly dynamic and organized process that serves many functions, most important of which is the correct expression of genes. The role that chromosome structure plays in gene regulation is an interesting and active area of study since we are just beginning to link specific chromosome structures to functional processes in the cell; an example of this is the looping of enhancer elements to gene promoters during transcription. Aberrant control of chromosome structure leads to many defects associated with the misregulation of genes including developmental syndromes, and the progression of tumors.

描述（由申请人提供）：细胞中基因表达的精确调控是一项重要任务，只有通过多个分子途径的协调才能完成。这些途径之一涉及染色体结构成分对转录的调节。染色体结构的异常控制与多种发育综合征、畸形和由于基因失调引起的肿瘤进展有关。最近的证据表明，染色体结构通过DNA环的形成与基因表达有关，DNA环在增强子环介导的转录过程中使增强子接近启动子。 干细胞是研究转录调控的理想细胞类型，因为它们具有独特的分化成生物体任何细胞类型的能力，也具有自我更新的能力。为了研究调控基因组转录的分子过程，我们将采用基于高通量基因组学的技术和方法。这项研究的目的是了解凝聚素，一种蛋白质复合物所需的结构维持染色体，在介导转录的作用。我们将绘制Condensin在基因组上的分布图，并确定负责Condensin募集和分布的因素。我们将研究Condensin与其他已知转录装置成员的全基因组占据模式，并将此模式与基因表达数据相关联。揭示染色体结构在转录中的功能仍然是一个尚未探索的研究领域，应该被认为是充分理解影响细胞基因表达程序的各种过程之间相互作用的关键。 公共卫生相关性：DNA包装成染色质是一个高度动态和有组织的过程，具有许多功能，其中最重要的是基因的正确表达。染色体结构在基因调控中的作用是一个有趣而活跃的研究领域，因为我们刚刚开始将特定的染色体结构与细胞中的功能过程联系起来;这方面的一个例子是转录过程中增强子元件与基因启动子的循环。染色体结构的异常控制导致许多与基因失调相关的缺陷，包括发育综合征和肿瘤的进展。