Multiscale Analyses of 4D Nucleome Structure and Function by Comprehensive Multimodal Data Integration

通过综合多模态数据集成对 4D 核组结构和功能进行多尺度分析

• 批准号: 10704567
• 负责人: Frank Alber
• 金额: $ 207.54万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704567
• 关键词: Address; Architecture; Binding; Biochemical; Cell Cycle; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Loop; Chromatin Structure; Chromosome Mapping; Chromosome Structures; Chromosomes; Collaborations; Communities; Complement; Computing Methodologies; Cytology; DNA Replication Timing; Data; Data Set; Development; Disease; Formulation; Gene Expression; Genetic; Genetic Transcription; Genome; Genomics; Goals; Health; Human; Image; Interphase Chromosome; Intuition; Knowledge; Link; Maps; Measurement; Measures; Methods; Microscopy; Mission; Modality; Modeling; Molecular; Multimodal Imaging; Nuclear; Nuclear Lamina; Nuclear Structure; Organelles; Outcome; Output; Phase; Population; Production; Public Health; Research; Research Personnel; Resolution; Role; Structure; Technology; Three-Dimensional Imaging; United States National Institutes of Health; Validation; Variant; Visualization; Work; cell fixing; cell type; computer framework; computerized tools; data exploration; data integration; data tools; empowerment; experimental study; genome-wide; genomic data; histone modification; imaging modality; improved; insight; machine learning algorithm; multi-scale atlas; multimodal data; multimodality; multiple data types; multiscale data; predictive modeling; response; spatiotemporal; superresolution microscopy; tool; transcription factor; transcriptome sequencing; user-friendly; whole genome

PROJECT SUMMARY The cell nucleus is a heterogeneous organelle that consists of nuclear bodies such as nuclear lamina, speckles, nucleoli and PML bodies. These structures continuously tether and tug chromatin at the small and large scales to synergistically orchestrate dynamic functions in distinct spatio-temporal compartments. A major obstacle to the production of navigable 4D reference maps and relating structure to function in the nucleus remains understanding how these different scales of organization influence each other. In particular, we have a poor understanding of the large-scale genome organization. Growing evidence suggests that such nuclear compartmentalization is causally connected with vital genome functions in human health and disease. However, the principles of this nuclear compartmentalization, its dynamics during changes in cell conditions, and its functional relevance are poorly understood. One lesson from Phase 1 4DN was the huge gap in throughput between imaging methods, that directly measure large-scale multi-landmark relationships, and genomic methods, that aim for whole genome high-resolution maps but are indirect measurements and provide limited information about large-scale compartments. For this 4DN UM1 Center application, we propose to meet these needs through the following Aims: (1) Generate multi-modal imaging and genomic datasets to reveal the structure, dynamics, and function of nuclear compartmentalization; (2) Develop and apply computational tools for data-driven genome structure modeling and integrative analysis of nuclear compartmentalization; (3) Develop an integrative analysis and visualization platform with navigable 4D reference maps of nuclear organization. The combined datasets and results of our proposed approaches will advance our understanding of nuclear compartmentalization, the interwoven connections among different nuclear components, and their functional significance. Our new integrative analysis tools and data-driven predictive models will produce more complete nuclear organization reference maps that integrate large-scale chromosome structure data from live and super-resolution microscopy with multi-modal genomic data including smaller scale chromatin interaction maps and predict functional relationships and dynamic responses. Our navigable reference maps will be publicly accessible through an analysis platform that provides interactive visualization of multiple data types, thus enabling investigators with diverse expertise to simultaneously explore their own data and related datasets/tools and promoting collaborations that will open new horizons into the role of the 4D nucleome in human health and disease.

项目摘要 细胞核是一种异质细胞器，由核体，例如核层， 斑点，核仁和PML体。这些结构在小的，在 在不同的时空隔室中协同编排动态函数的大尺度。专业 生产可通航的4D参考图的障碍以及在核中起作用的结构 仍然了解这些不同的组织规模如何相互影响。特别是，我们有一个 对大规模基因组组织的了解不足。越来越多的证据表明这种核 分室化与人类健康和疾病中重要的基因组功能有因果关系。 但是，这种核分室化的原理，其在细胞条件变化中的动态， 它的功能相关性知之甚少。第1阶段4DN的一堂课是巨大的差距 成像方法之间的吞吐量，直接测量大规模的多地标关系， 基因组方法，旨在整个基因组高分辨率图，但是间接测量的，并提供 有限的有关大型隔间的信息。对于此4DN UM1中心申请，我们建议见面 通过以下目的这些需求：（1）生成多模式成像和基因组数据集以揭示 核分区化的结构，动力和功能； （2）开发和应用计算工具 用于数据驱动的基因组结构建模和核分室化的综合分析； （3） 使用可通航的4D参考图来开发一个集成分析和可视化平台 组织。我们提出的方法的组合数据集和结果将提高我们的理解 核分室化，不同核成分之间的交织连接及其之间的连接 功能意义。我们新的集成分析工具和数据驱动的预测模型将产生更多 完整的核组织参考图，这些图整合了现场的大规模染色体结构数据 以及具有多模式基因组数据（包括较小比例染色质相互作用）的超分辨率显微镜 地图并预测功能关系和动态响应。我们可通航的参考地图将是 通过分析平台公开访问，该平台提供多种数据类型的交互式可视化， 因此，使具有多样专业知识的研究人员同时探索自己的数据和相关 数据集/工具和促进合作，这些合作将为4D核心在4D中的作用开放 人类健康和疾病。