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Combined Cytological, Genomic, and Functional Mapping of Nuclear Genome Organization

核基因组组织的联合细胞学、基因组和功能作图

基本信息

批准号：
9769714
负责人：
Andrew Steven Belmont
金额：
$ 161.63万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2015-09-28 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769714
关键词：
Anatomy Back Bioinformatics Biological Assay Biological Process Biology Cell Line Cell Nucleus Cells Chromatin Chromosomes Complement Computer Simulation Custom Cytology DNA DNA Sequence Data Data Set Elements Environment Epigenetic Process Fiber Frequencies Gene Expression Regulation Genetic Genome Genomic Segment Genomics Goals Grant Heterochromatin Investigation Link Location Maps Measures Messenger RNA Methodology Methods Microscopy Modeling Molecular Nuclear Nuclear Export Nuclear Lamina Nuclear Structure Organelles Property RNA Splicing Reagent Research Research Personnel Resources Series Site Specific qualifier value Structure Techniques Technology Validation base design experience genome-wide genomic data innovation live cell microscopy mammalian genome predictive modeling promoter public health relevance spatial relationship

项目摘要

DESCRIPTION: Decades of microscopy have revealed that the nucleus is not a homogeneous organelle, but rather consists of distinct compartments such as nucleoli, nuclear speckles, the nuclear lamina, among other structures. Increasing evidence indicates that specific genomic regions each associate with these compartments. This genome compartmentalization has been linked to various functions, but these links are still poorly understood. Interestingly, Lamina Associated Domains (LADs) share specific heterochromatin marks, defining chromatin domains with distinct genetic and epigenetic properties. Genomic regions associating with other nuclear compartments may similarly define distinct classes of chromatin domains. One major bottleneck towards a deeper understanding of nuclear organization has been the inability to convert microscopy views of nuclear compartments into genome-wide maps that show which loci are associated with which compartment, and how the chromosomal fiber traverses between compartments. In addition, there is an urgent need for more efficient methods to dissect the mechanisms by which large genomic regions are targeted to specific nuclear compartments. Finally, there is an urgent need for high-throughput approaches that query the functional relevance of genome compartmentalization. For this Center grant, we propose to meet these needs through the following Aims: 1. Develop a strategy that connects microscopy views to genome-wide maps that, together with modeling, reveal the localization and dynamics of genomic regions relative to all major nuclear compartments. 2. Develop methods for efficient manipulation of the genome in order to elucidate mechanisms that target loci to specific compartments. 3. Develop methods to measure, model, and validate the functional relevance of nuclear compartments. The combined results of these approaches will reveal causal relationships now hidden among entangled genomic, epigenetic, and nuclear organization features. Deliverables of this proposal include a wide range of structural and functional maps of nuclear organization, reagents for visualizing endogenous chromosome loci, a powerful pipeline for synthesis of ~100kb DNA fragments, and cell lines facilitating repeated, high-fidelity insertio of these large fragments back into selected sites in the genome. These resources will provide a powerful complement to other 4D Nucleome Consortium efforts. A key strength of this Center proposal is the experience and complementary research capabilities of its five Investigators. Together they will pool their expertise for a concerted investigation into the biological functions of nuclear compartmentalization.