Center for Integrated Multi-modal and Multi-scale Nucleome Research

综合多模式和多尺度核组研究中心

基本信息

批准号：
10269034
负责人：
Catherine Dulac
金额：
$ 130万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-09-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269034
关键词：
3-Dimensional Acute Address Affect Architecture Atlases Biological Biological Assay Brain Brain region CRISPR interference Cell Nucleus Cells Chromatin Chromatin Modeling Chromatin Structure Communities Complex Data Development Distal Elements Enhancers Foundations Free Will Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Goals Hippocampus (Brain)Human Human Genome Hypothalamic structure Image Imaging Device Individual Knowledge Macaca Mammalian Cell Mammals Maps Measurable Methods Modeling Monkeys Mus Nuclear Physics Physiological Play Polymers Regulator Genes Research Research Personnel Research Project Grants Resolution Role Scientist Slice Social Behavior Structural Models Structure Technology Testing Tissues Transcriptional Regulation Untranslated RNA Virtual and Augmented reality Visualization analytical tool base cell type cohesin embryonic stem cell epigenome epigenomics experimental study genomic data high resolution imaging improved informatics tool insight learning strategy mammalian genome multimodality nanoscale nerve stem cell nervous system disorder neural circuit new technology predictive modeling predictive test programs promoter statistical learning tool transcriptomics virtual reality web portal

项目摘要

The transcriptional regulatory sequences communicate with each other dynamically in the 3D nuclear space to direct cell type specific gene expression. Currently, a major barrier to understanding the transcriptional regulatory programs is the lack of tools, models and maps to explore the chromatin architecture in diverse cell types and physiological contexts. We will address this pressing need by deploying transformative technologies to study the chromatin architecture in mammalian cells at an unprecedented resolution and scale. Specifically, we will generate navigable, cell-type-specific reference maps of chromatin architecture in the mouse, macaque and human brains by integrating high resolution and high throughput imaging and orthogonal single-cell-based genomic methods. We will also dissect the role of chromatin architecture in gene regulation through a set of controlled perturbation experiments in the mouse ES cells (ESC) and ESC-derived neural progenitor cells (NPC). We will develop structural models of chromatin organization with advanced polymer physics and statistical learning methods, and validate their predictive power in embryonic stem cells and in ex vivo brain slices. Finally, we will make the reference maps, analytical tools, visualization methods and structural models available to the broader community. The proposed research project will dramatically transform our ability to analyze the 4D Nucleome of complex tissues, and produce the much-needed maps, tools and models for understanding the gene regulatory programs encoded in the linear genome sequences.

转录调控序列在 3D 核空间指导细胞类型特异性基因表达。目前，一个主要障碍是了解转录调控程序缺乏工具、模型和图谱探索不同细胞类型和生理环境中的染色质结构。我们将通过部署变革性技术来研究这一迫切需求以前所未有的分辨率和规模研究哺乳动物细胞中的染色质结构。具体来说，我们将生成可导航的、特定于细胞类型的染色质参考图通过集成高分辨率和人类大脑的结构高通量成像和正交单细胞基因组方法。我们还将通过一组受控的结构剖析染色质结构在基因调控中的作用小鼠 ES 细胞 (ESC) 和 ESC 衍生的神经祖细胞的微扰实验细胞（NPC）。我们将利用先进的技术开发染色质组织的结构模型聚合物物理和统计学习方法，并验证它们的预测能力胚胎干细胞和离体脑切片。最后，我们将制作参考图，分析工具、可视化方法和结构模型可供更广泛的人使用社区。拟议的研究项目将极大地改变我们的分析能力复杂组织的 4D 核组，并生成急需的图谱、工具和用于理解线性基因组中编码的基因调控程序的模型序列。