Mapping the 3D Genome Landscape

绘制 3D 基因组景观图

• 批准号: 9021520
• 负责人: Frank Alber
• 金额: $ 80万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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/9021520
• 关键词: Adopted; Architecture; Atlases; Automobile Driving; Biological; Biology; California; Cell Nucleus; Cell physiology; Cells; Chemicals; Chromatin; Chromosomes; Code; Collaborations; Communities; Complex; Computing Methodologies; DNA; DNA biosynthesis; Data; Defect; Disease; Enhancers; Ensure; Freezing; Gene Cluster; Gene Expression; Genome; Genomic DNA; Institutes; Language; Link; Maps; Mass Spectrum Analysis; Methods; Modeling; Molecular Conformation; Noise; Nuclear; Nucleic Acids; Pathologic Processes; Physiological Processes; Play; Positioning Attribute; Process; Protein Dynamics; Proteins; Protocols documentation; Reading; Reagent; Recording of previous events; Relative (related person); Research; Research Personnel; Resources; Series; Software Tools; Solid; Staging; Structure; Structure-Activity Relationship; Surface; T cell differentiation; T-Lymphocyte; Techniques; Technology; Three-dimensional analysis; Time; Transcription Process; Universities; Validation; Variant; computerized tools; data acquisition; design; genome-wide; improved; innovation; insight; member; new technology; novel; novel strategies; population based; promoter; protein complex; public health relevance; technology development; technology/technique; temporal measurement; three dimensional structure; three-dimensional modeling; tool

 DESCRIPTION: The 3D structural organization of the genome plays a key role in nuclear functions such as gene expression and DNA replication. One of the next grand challenges of biology is to determine the detailed 3D genome architecture and elucidate its functional implications. In this proposal, we aim to develop a suite of novel technologies for comprehensive structural and dynamic analyses of genomes, in two aspects: (1) the spatial interactions and higher-order organization of genomic DNA and (2) the functional organization of protein complexes driving the 3D folding of genomes. The new computational and experimental methods proposed herein integrate multiple experimental inputs and generate physical higher-order models of the 3D nuclear genome organization. Analysis of these models will yield new insights into the principles and structure/functions relationships of the genome's 3D organization in space and time. We have the following aims: (1) Develop technologies for mapping the relative spatial positions of genomic DNA in the nucleus: our focus will be on the three major technical barriers faced by all current mapping technologies, namely inefficient and potentially biased data acquisition, lack of temporal resolution, and missing higher-order contact information. (2) Develop technologies for deciphering the "Protein Code" of 3D genome organizations: we will employ a proven pipeline for the isolation of native protein complexes, but extensively optimized for the purpose of reading out the chromatin interactome surrounding each particular chromatin interacting region. (3) Develop technologies for modeling and analysis of 3D genome structures: we will develop an integrated platform for population-based modeling of 3D genome structures, and develop a series of computational tools to perform structure-function mapping on the 3D genomes. (4) Develop sold validation techniques for guiding the above technology innovations: we will develop a set of simple-to-implement and easy-to-interpret techniques to validate our novel technologies, and this techniques can be generally adopted by the community for similar validation purposes.

 描述：基因组的 3D 结构组织在基因表达和 DNA 复制等核功能中发挥着关键作用。生物学的下一个重大挑战之一是确定详细的 3D 基因组结构并阐明其功能含义。在本提案中，我们的目标是开发一套用于基因组全面结构和动态分析的新技术，包括两个方面：（1）基因组DNA的空间相互作用和高阶组织；（2）驱动基因组3D折叠的蛋白质复合物的功能组织。本文提出的新计算和实验方法集成了多个实验输入并生成 3D 核基因组组织的物理高阶模型。对这些模型的分析将对基因组在空间和时间上的 3D 组织的原理和结构/功能关系产生新的见解。我们的目标如下：（1）开发绘制细胞核中基因组DNA相对空间位置的技术：我们的重点将放在当前所有绘图技术面临的三大技术障碍上，即低效且可能存在偏差的数据采集、缺乏时间分辨率以及缺失高阶联系信息。 (2) 开发破译 3D 基因组组织“蛋白质密码”的技术：我们将采用经过验证的管道来分离天然蛋白质复合物，但为了读出每个特定染色质相互作用区域周围的染色质相互作用组而进行了广泛优化。 （3）开发3D基因组结构建模和分析技术：开发基于群体的3D基因组结构建模集成平台，并开发一系列计算工具来对3D基因组进行结构功能映射。 （4）开发可销售的验证技术来指导上述技术创新：我们将开发一套易于实现且易于解释的技术来验证我们的新技术，并且该技术可以被社区普遍采用以用于类似的验证目的。