Center for 3D Structure and Physics of the Genome

基因组 3D 结构和物理中心

• 批准号: 9150549
• 负责人: Job Dekker
• 金额: $ 265.07万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150549
• 关键词: Architecture; Base Sequence; Benchmarking; Biological; Biological Process; Cell Cycle; Cell Cycle Stage; Cell Differentiation process; Cell Nucleus; Cells; Cellular biology; Chromatin; Chromatin Fiber; Chromatin Loop; Chromosome Structures; Chromosomes; Collaborations; Complement; Computational Biology; Computer Simulation; DNA Repair; DNA biosynthesis; Data; Defect; Detection; Development; Diabetes Mellitus; Elements; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Genomics; Goals; Homeostasis; Human Genome; Image; Interphase; Investigation; Laboratories; Lead; Length; Life; Light; Link; Maintenance; Malignant Neoplasms; Maps; Mechanics; Methodology; Methods; Microscopy; Mitosis; Modeling; Molecular; Molecular Biology; Molecular Conformation; Nuclear; Nucleic Acids; Nucleosomes; Pattern; Physical condensation; Physics; Polymers; Population; Process; Property; Proteins; Proteome; Recording of previous events; Regulation; Research; Resolution; Role; Signal Transduction; Site; Structure; Technology; Validation; base; biophysical model; chromosome conformation capture; comparative; computerized tools; data integration; daughter cell; developmental disease; genome editing; genome-wide; genome-wide analysis; histone modification; human disease; imaging genetics; imaging platform; improved; innovation; insight; live cell imaging; live cell microscopy; mammalian genome; multidisciplinary; novel strategies; physical model; public health relevance; single cell analysis; stem cell differentiation; three dimensional structure; three-dimensional modeling; tool; transcriptome; transmission process

 DESCRIPTION: The spatial organization of the genome impinges on all genomic processes, including gene regulation, maintenance of genome stability and chromosome transmission to daughter cells. A detailed understanding of the spatial arrangement of the human genome, referred to as the 4D nucleome, and the biological and physical principles that drive chromosome folding requires combining approaches from the fields of molecular and cell biology, imaging, genetics and genomics with approaches from physics, computational biology, and computer simulation. We have assembled a highly interdisciplinary center with the goal of generating extensively validated maps of the 4D nucleome, its physical and dynamic properties and its role in regulating the activity of the genome. First, the center will further optimize and extensively validate a suite of genome-wide molecular methodologies, based on chromosome conformation capture (3C) that can probe the folding of chromosomes at the scale of single nucleosomes, chromatin fibers, chromosomes and the entire nucleus, across cell populations and in single cells. Given that chromosome and nuclear organization is tightly linked to biological state of the cell, the center will map the 4D nucleome for four key biological states representing different conformations during the cell cycle (interphase and mitosis), and during cell differentiation (pluripotent and differentiated states). We will obtain complementary data regarding the structure and dynamics of chromatin, at different length scales and in single cells using extensive high-throughput imaging, live cell imaging and super resolution microscopy. Data obtained with all approaches will be analyzed, integrated and modeled using a set of methods we will further develop to gain insights into the structure, physics and dynamics of chromosome folding over different length scales. Finally, a critical component of our proposal is the biological validation and further elaboration of the chromatin interaction maps that are generated from our conformational analyses. This validation will be achieved through site-specific editing of genomic sequence and epigenetic marks, the creation of new contact points within the genome, and the identification of factors (both protein and nucleic acid) that facilitat or restrict these interactions. Effects of such perturbations in the chromosome conformation on transcription will reveal relationships between specific chromosome structural features and gene expression.

 描述：基因组的空间组织影响到所有基因组过程，包括基因调控、维持基因组稳定性和将染色体传递给子代细胞。要详细了解人类基因组的空间排列，即4D基因组，以及驱动染色体折叠的生物学和物理原理，需要将分子和细胞生物学、成像、遗传学和基因组学领域的方法与物理学、计算生物学和计算机模拟的方法结合起来。我们已经组建了一个高度跨学科的中心，目标是生成4D核基因组的广泛验证的图谱，它的物理和动力学性质以及它在调节基因组活动中的作用。一是中心将进一步优化和优化 广泛验证一套基于染色体构象捕捉(3C)的全基因组分子方法，该方法可以探测单核小体、染色质纤维、染色体和整个细胞核、跨细胞群体和单细胞的染色体折叠。鉴于染色体和核组织与细胞的生物状态密切相关，该中心将绘制代表细胞周期(间期和有丝分裂)和细胞分化(多能和分化状态)期间不同构象的四个关键生物状态的4D核组。我们将使用广泛的高通量成像、活细胞成像和超分辨率显微镜，在不同长度的尺度上和在单细胞中获得关于染色质结构和动力学的补充数据。使用所有方法获得的数据将使用一套我们将进一步开发的方法进行分析、集成和建模，以深入了解不同长度尺度上的染色体折叠的结构、物理和动力学。最后，我们建议的一个关键组成部分是对我们的构象分析产生的染色质相互作用图进行生物学验证和进一步细化。这种验证将通过对基因组序列和表观遗传标记进行定点编辑，在基因组内创建新的接触点，以及确定促进或限制这些相互作用的因素(蛋白质和核酸)来实现。染色体构象的这种扰动对转录的影响将揭示特定的染色体结构特征与基因表达之间的关系。