New automated experimental and computational pipeline for high coverage single-cell Hi-C and its integration with single cell RNA-seq: enabling 4D Nucleomics at single cell resolution

用于高覆盖率单细胞 Hi-C 的新自动化实验和计算流程及其与单细胞 RNA-seq 的集成：以单细胞分辨率实现 4D 核组学

• 批准号: 9144845
• 负责人: Peter J Fraser
• 金额: $ 38.13万
• 依托单位: BABRAHAM INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144845
• 关键词: Alleles; Automation; Biochemical; Biological Assay; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Cell Differentiation process; Cell Nucleus; Cells; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Chromosome Structures; Chromosome Territory; Chromosomes; Communities; Complex; Computer Analysis; Computer Simulation; Computer software; Data; Data Analyses; Data Set; Development; Diploid Cells; Disease; Ensure; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Profile; Generations; Genes; Genome; Genome Components; Genomics; Goals; Haplotypes; Health; Hematological Disease; Hematopoietic; Histocompatibility Testing; Human; Hybrids; Immune system; Individual; Knowledge; Libraries; Ligation; Malignant Neoplasms; Maps; Measures; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mus; Nuclear; Pattern; Phase; Planet Mars; Play; Population; Prevention; Protocols documentation; Publishing; Qualifying; Reading; Recovery; Research; Resolution; Role; Staging; Statistical Methods; Structure; Structure-Activity Relationship; Techniques; Technology; Therapeutic; Tissues; Work; adult stem cell; base; cell type; cellular imaging; design; effective therapy; genome analysis; genome-wide; improved; insight; invention; next generation; research study; single cell analysis; stem; three dimensional structure; three-dimensional modeling; tool; transcriptome; transcriptome sequencing; treatment strategy; whole genome

 DESCRIPTION (provided by applicant): In this project we will develop new methods to investigate the three dimensional arrangement of the genome in various cell types from mouse bone marrow. The three dimensional organization of the genome, how it is physically arranged in the nucleus of cells, is recognized as an important component of genome control. The mechanisms by which genes get switched on and off in the correct cells or tissue type, and during the correct stages of development include changes in the spatial organization of the genome. We will develop a new method that can assess three dimensional genome organizations in thousands of individual cells and simultaneously measure the actual gene expression profile of a large number of those cells. We will systematically analyze the data mathematically and statistically to look for new principles of genome organization that may play unknown roles in controlling the genome in health and disease. We will also use the data to generate 3D computer models of individual chromosomes and the entire genome as it exists in the individual cell nucleus. We will then use these models to look for spatial patterns, recurring structures and variable structured regions of the genome that may be important in gene control. For these experiments we will use mouse bone marrow cells, which are an important representative of human bone marrow cells. Bone marrow is a clinically important, complex tissue containing the adult stems cells that give rise to all cells of the blood and immune system. By systematically analyzing the 3D genome conformation and gene expression profiles of these important cell types we will be providing fundamental knowledge of how these cell types function to create the blood. We will cooperate with other research groups to ensure that they have access to these powerful technologies and computer analysis packages that will accelerate a fuller understanding of how the genome is controlled. This information is vital to design new effective therapeutic strategies for the treatment of diseases of the blood and other tissues, and to understand the molecular basis of cancers for more effective treatments and prevention.

 描述（由适用提供）：在此项目中，我们将开发新的方法来研究小鼠骨髓各种细胞类型中基因组的三维布置。基因组的三维组织，如何在细胞核中物理排列，被认为是基因组控制的重要组成部分。基因以正确的细胞或组织类型打开和关闭基因的机制，在正确的发育阶段，包括基因组空间组织的变化。我们将开发一种可以评估数千个单个细胞中三维基因组组织的新方法，并简单地测量大量细胞的实际基因表达谱。我们将在数学上和统计上系统地分析数据，以寻找可能在控制健康和疾病中的基因组中发挥未知作用的基因组组织的新原理。我们还将使用数据来生成单个染色体的3D计算机模型和整个基因组，因为它存在于单个细胞核心中。然后，我们将使用这些模型来寻找在基因控制中可能很重要的基因组的空间模式，重复结构和可变结构化区域。对于这些实验，我们将使用小鼠骨髓细胞，这是人骨髓细胞的重要代表。骨髓是一种临床上重要的，含有成年茎的复杂组织，是引起血液和免疫系统所有细胞的细胞。 通过系统地分析这些重要细胞类型的3D基因组会议和基因表达谱，我们将提供有关这些细胞类型如何发挥血液的基本知识。我们将与其他研究小组合作，以确保他们能够访问这些强大的技术和计算机分析软件包，以加速对基因组的控制方式。该信息对于设计新有效的治疗策略至关重要，以治疗血液和其他组织的疾病，并了解癌症的分子基础以进行更有效的治疗和预防。