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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结