Center for 3D Structure and Physics of the Genome

基因组 3D 结构和物理中心

• 批准号: 9353819
• 负责人: Leonid A Mirny
• 金额: $ 34.57万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9353819
• 关键词: Address; Agreement; Alleles; Bacterial Chromosomes; Binding; Biological; Cell Cycle; Cells; Characteristics; Chromatin; Chromosome Structures; Chromosomes; Data; Data Analyses; Development; Elements; Epigenetic Process; Frequencies; Gene Expression; Genome; Genome engineering; Genomics; Human; Human Chromosomes; Image; Knowledge; Maps; Methods; Microscopy; Mitotic Chromosome; Modeling; Molecular; Morphology; Pattern; Physical condensation; Physics; Polymers; Positioning Attribute; Proteins; Resolution; Signal Transduction; Structure; Techniques; Technology; Validation; Variant; base; cell type; comparative; computerized data processing; computerized tools; data integration; data modeling; experimental study; human data; imaging approach; mechanical properties; method development; physical model; three dimensional structure; tool

PROJECT SUMMARY – Data Analysis and Modeling Despite the growing quantity and resolution of chromosome interaction data our understanding of physical principles underling chromosomal organization and its connection with genomic function remain limited. Mapping of chromosomal interactions proposed in Component 2, will provide large amounts of data from a variety of methods that each address its own aspect and range of scales of chromosomal organization. Further progress, however, relies on our ability to bridge between these new data and 3D physical models of chromosomes that can reveal principles of genome folding. We will continue development of methods for processing, correction and analysis of data from Hi-C- based technologies, as well as development of polymer models of chromosomal organization that have been successful in reproducing Hi-C and microscopy data for human and bacterial chromosomes, and have been able to reveal structural elements not immediately visible in the data. Here we propose to take a full advantage of the new mapping technologies and further develop our physics-based approach to address several challenges in understanding biological mechanisms and physical principles of chromosomes folding. Modeling will also provide a natural platform for integration of interaction and imaging data. First, we will develop computational tools for processing data produced by new Hi-C-based technologies, (micro-C, high-resolution Hi-C, allele-specific Hi-C and single-cell Hi-C), and integrate data across scales into Integrated Interaction Maps. Second, we will develop computational tools to analyze Interaction Maps produced by new Hi-C-based technologies, aiming to reveal structural elements of human chromosomes at different scales. Third, we will develop polymer models that will allow validation of Hi-C interaction maps by HIPMap microscopy data, as proposed in Component 2. Finally, we will develop a comprehensive multi-scale polymer model of human chromosomal organization, comparing it to new interaction data at every scale. All models and discovered principles of organization will be systematically validated using imaging, genome engineering, and micromechanical experiments as outlined in Components 4 and 5.

项目概要-数据分析和建模 尽管染色体相互作用数据的数量和分辨率不断增加， 染色体组织的基本原理及其与基因组功能的联系仍然有限。 在组件2中提出的染色体相互作用的绘图将提供来自各种各样的基因组的大量数据。 每种方法都针对其自身的染色体组织的方面和范围。进一步的进展， 然而，依赖于我们在这些新数据和染色体的3D物理模型之间建立桥梁的能力， 可以揭示基因组折叠的原理 我们将继续开发处理、校正和分析Hi-C数据的方法， 的技术，以及染色体组织的聚合物模型的发展， 成功地复制了人类和细菌染色体的Hi-C和显微镜数据， 能够揭示数据中无法立即看到的结构元素。在这里，我们建议充分利用 新的映射技术，并进一步发展我们的物理为基础的方法，以解决几个 理解染色体折叠的生物学机制和物理原理面临的挑战。建模 还将为交互和成像数据的集成提供自然平台。 首先，我们将开发计算工具，用于处理新的基于Hi-C的 技术，（微C，高分辨率Hi-C，等位基因特异性Hi-C和单细胞Hi-C），并整合数据 整合成集成交互地图。其次，我们将开发计算工具来分析 由基于Hi-C的新技术产生的交互图，旨在揭示人类的结构元素 不同比例的染色体第三，我们将开发聚合物模型，以验证Hi-C 根据组件2中的建议，通过HIPMap显微镜数据绘制相互作用图。最后，我们将开发一个 人类染色体组织的综合多尺度聚合物模型，将其与新的 每个尺度的交互数据。所有的模型和发现的组织原则将被系统地 使用组件4中概述的成像、基因组工程和微机械实验进行验证 和5.