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Integrative single-cell spatial genomic, transcriptomic, and epigenetic imaging in mammalian tissue

哺乳动物组织中的综合单细胞空间基因组、转录组和表观遗传成像

基本信息

批准号：
10027392
负责人：
Siyuan Wang
金额：
$ 53.49万
依托单位：
YALE 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：
2020-08-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10027392
关键词：
3-Dimensional Address Adult Affect Aging Architecture Biological Assay Biological Process Biomedical Research Cell Culture Techniques Cell Nucleolus Cell Nucleus Cell physiology Cells Chromatin Chromatin Loop Chromosome Territory Chromosomes Communities Complex Computer software DNA DNA Binding Data Display Development Disease Enhancers Epigenetic Process Fluorescent in Situ Hybridization Future Gene Expression Gene Expression Regulation Genetic Transcription Genome Genomic DNA Genomic Segment Genomics Health Human Development Human body Image Imaging technology In Situ In Vitro Length Malignant Neoplasms Mammalian Cell Maps Measurement Measures Methodology Methods Mus Nuclear Nuclear Lamina Pattern Process Progeria RNA Research Research Personnel Resolution Structure Techniques Technology Testing Three-dimensional analysis Time Tissues Visualization Work base cell behavior cell type combinatorial design epigenome experience experimental study fetal genome-wide genomic locus genomic profiles multiplexed imaging novel novel strategies nuclear imaging promoter protein distribution single molecule structural genomics transcriptomics user friendly software virtual

项目摘要

Project Summary/Abstract The three-dimensional (3D) organization of the genome affects many genomic functions. Multiple 3D genome architectures at different length scales, including chromatin loops, domains, compartments, and regions associated with nuclear lamina and nucleoli, have been discovered. Changes in these architectures have been associated with normal development, aging, and a wide range of diseases. However, how these structures are arranged in the same cell, how they vary in different cell types in mammalian tissue, and how they are correlated with gene expression and the epigenome in the tissue contexts are largely unknown. Current approaches are severely limited by a lack of capacity to simultaneously trace chromatin folding across multiple length scales, measure genomic organization in relation to other nuclear components, and profile gene expression and epigenome in the same single cells in mammalian tissue. To address this need, here we propose to develop a new methodology, termed Multiplexed Imaging of Nucleome Architectures (MINA), which will enable simultaneous measurements of multiscale chromatin folding, associations of genomic regions with nuclear lamina, nucleoli and other nuclear/epigenetic components, and copy numbers of numerous RNA species in the same, single cells in mammalian tissue. We expect this development to broadly impact many lines of research on 3D genomics by depicting cell-type-specific multiscale genomic architectures associated with gene expression and epigenome, in different types of tissue undergoing different biological processes. Furthermore, by allowing measurements within the same cell, it will in future be possible to directly test the causal relationship between genomic architecture and gene expression, thus opening up a completely new experimental paradigm to identify novel mechanisms that regulate gene expression across human development, health and disease.

项目总结/摘要基因组的三维（3D）组织影响许多基因组功能。多重三维基因组不同长度尺度的结构，包括染色质环、结构域、区室和区域与核纤层和核仁相关的蛋白质。这些架构中的变化与正常发育、衰老和各种疾病有关。然而，这些结构是如何的它们在哺乳动物组织的不同细胞类型中是如何变化的，以及它们是如何在同一个细胞中排列的。与基因表达和组织环境中的表观基因组相关的基因组在很大程度上未知。电流这些方法由于缺乏同时追踪多个染色质折叠的能力而受到严重限制。长度尺度，测量与其他核组分相关基因组组织，并分析基因表达和表观基因组在哺乳动物组织中的相同单细胞中。为了满足这一需求，我们我建议开发一种新的方法，称为核组结构的多重成像（MINA），将能够同时测量多尺度染色质折叠，基因组区域与核纤层、核仁和其他核/表观遗传成分，以及大量RNA的拷贝数在哺乳动物组织的同一个单细胞中。我们预计这一发展将广泛影响许多通过描绘细胞类型特异性的多尺度基因组结构，基因表达和表观基因组，在不同类型的组织经历不同的生物过程。此外，通过允许在同一小区内进行测量，将来将有可能直接测试基因组结构和基因表达之间的因果关系，从而开辟了一个全新的实验范式，以确定新的机制，调节基因表达在人类发展、健康和疾病。