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Nucleome Positioning System for Spatiotemporal Genome Organization and Regulation

用于时空基因组组织和调控的核组定位系统

基本信息

批准号：
9020494
负责人：
YIJUN RUAN
金额：
$ 74.98万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
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/9020494
关键词：
Address Algorithms Architecture Biological Biological Models Cell Count Cell Line Cell Lineage Cell Nucleus Cell Separation Cell physiology Cells Chromatin Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Communities Complement 3d Complex Computational Biology Computer Simulation Data Data Analyses Data Quality Data Set Development Disease Elements Enhancers Future Gene Expression Gene Expression Profile Gene Expression Regulation Generations Genetic Genome Genome Mappings Genomics Geometry Goals Guidelines Haplotypes Health Hematopoietic Hereditary Disease Human Human Cell Line Human Genome Image Imagery Imaging Device Imaging technology Immune Immune response Immunology In Vitro Individual Investigation Knock-out Label Libraries Life Lymphocyte Maps Mediating Methodology Methods Microfluidics Microscopy Miniaturization Modeling Molecular Biology Monitor Nuclear Nuclear Structure Positioning Attribute Positron-Emission Tomography Preparation Process Proteins Publications Regulation Regulatory Element Research Research Personnel Resolution Role Sampling Stimulus Structure System Techniques Technology Time Tn5 transposase Training Untranslated RNA Validation Whole Blood Work base biological systems cell type cellular imaging data modeling epigenome genome editing genome wide association study genome-wide imaging modality improved in vivo insight interest miniaturize mouse model process optimization promoter public health relevance response spatiotemporal technology development three dimensional structure three-dimensional modeling tool

项目摘要

DESCRIPTION: This proposal seeks to fulfill a community need for a comprehensive, high-resolution genome-mapping platform that will enable investigation of the structural, functional and spatiotemporal organization of the human genome. Our ultimate goal is to deliver complex chromatin interaction network maps in the context of 3D genome structures from which the dynamics of individual genomic elements can be monitored and referenced. Here, we propose to develop a Nucleome Positioning System (NPS)-comprised of 1) a robust genome- wide mapping technology platform, 2) advanced computational modeling algorithms and 3) state-of-the-art nuclear imaging methods-that will allow users community-wide to uncover the regulatory functions of 3D genome organization in human cells. NPS will be based upon the established ChIA-PET method (1,2), enhanced by process optimizations-i.e., microfluidic-based miniaturization and Tn5-transposase-based library preparation-to facilitate the study of chromatin interactions mediated by protein factors across a broader range of human cell types (Aim 1, see also Mapping Technology Development Component). We will also optimize RICh-PET for the comprehensive mapping of chromatin interactions mediated by non-coding RNAs (Aim 1). The high-quality mapping data generated through these optimization efforts will be analyzed by a new computational platform (Three-Dimensional Nucleome Modeling Engine, or 3D-NOME) that makes use of hierarchical multi-scaling to model 3D genome structures (Aim 2, Data Analysis and Modeling component). We will also complement the 3D modeling with transcriptome, epigenome and SNP data associated with genetic diseases (GWAS) to provide functional annotation to structural units (Aim 2). We will continue by developing strategies to validate the nucleome geometry predicted by 3D-NOME both structurally, using new nuclear imaging technologies, and functionally, using cutting-edge genome- and epigenome-editing approaches, in both human cell lines and mouse models (Aim 3, Biological Validation Component). Finally, we will implement NPS to generate pilot 3D genome maps from a wide range of human cell lines and primary immune cells sorted from whole blood, to elucidate the spatiotemporal dynamics of human genome organization over major developmental and hematopoietic cell lineages, as well as among differentiating lymphocytes involved in the immune response (Aim 4, Data Generation Component). Together, these efforts will yield a powerful set of sophisticated, high-quality tools and mapping data for the larger research community, and will help establish the standards for future 3D/4D nucleome studies. They will also provide insights into the broad mechanisms that organize the structure and regulate the function of the human genome, as well as the specific mechanisms by which immune responses are regulated at the nuclear level.