University of Washington Center for Nuclear Organization and Function

华盛顿大学核组织与功能中心

• 批准号: 9983850
• 负责人: William Stafford Noble
• 金额: $ 27.7万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983850
• 关键词: 3-Dimensional; Acute; Address; Algorithms; Alleles; Architecture; Area; Benchmarking; Binding; Biological; Biological Assay; Biological Models; Biology; CRISPR/Cas technology; Cardiac Myocytes; Cardiomyopathies; Cell Cycle; Cell Differentiation process; Cell Line; Cell Nucleus; Cell physiology; Cells; Chromosomes; Communities; Computer Simulation; Computer software; Computing Methodologies; Coupled; DNA; DNA biosynthesis; Data; Data Set; Deoxyribonucleases; Development; Dimensions; Diploidy; Disease; Down Syndrome; Endothelial Cells; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Genomics; Haploidy; Health; Heterogeneity; Human; Human Biology; Human Cell Line; Human Genome; Hybrids; Induced Mutation; K-562; Lamin Type A; Leadership; Link; Maps; Measures; Mediating; Methodology; Methods; Modeling; Molecular Conformation; Mus; Nature; Nuclear; Nuclear Matrix-Associated Proteins; Output; Population; Procedures; Process; Protocols documentation; Research Personnel; Resolution; Role; Side; Skeletal Myoblasts; Standardization; Structure; System; Technology; Testing; Time; Tissues; Universities; Validation; Washington; Work; base; biological systems; combinatorial; embryonic stem cell; genome editing; genomic data; human disease; human embryonic stem cell; improved; in vivo; indexing; innovation; insight; method development; novel; open source; predictive modeling; programs; public health relevance; response; restriction enzyme; single cell analysis; single-cell RNA sequencing; technology development; three-dimensional modeling; tool; transcription factor; transcriptome sequencing

 DESCRIPTION: A current grand challenge in genomics involves accurately assaying, at all relevant scales, the 3D conformation of DNA in vivo and then linking conformational changes to dynamic processes such as the cell cycle, differentiation and disease. Here we propose to create the University of Washington Center for Nuclear Organization and Function, bringing together an interdisciplinary team of investigators whose diverse areas of expertise - technology development, computational modeling, and mouse and human biology - make them ideally suited to this challenge. Our overall hypothesis is that characterizing and understanding changes in genome architecture over time (the 4D nucleome) will lead to fundamental insights into human biology and disease. We will address this hypothesis by developing a combination of experimental and computational methods development, coupled with their systematic biological validation and application to development- and disease-relevant systems. On the experimental side, we will further optimize our recently developed DNase Hi- C assay, including combinatorial methods for single cells, ultimately aiming to concurrently assay nuclear architecture and gene expression within each of many single cells. On the computational side, we will extend our existing 3D modeling algorithms to account for diploidy, cell-to-cell variabilit, the hierarchical nature of genome architecture, and to explicitly model architectural changes over cell cycle and cell differentiation time scales. We will then employ several complementary computational methods to link our 4D nucleome models to existing, 1D genomics data sets. The outputs of these new experimental and computational technologies will be subjected to orthogonal validation in several well-understood model systems: human cell lines, in vivo tissues from interspecific F1 hybrid mice, mouse embryonic stem cells (ESCs) and skeletal myoblasts. We will also test specific predictions of the models in response to targeted (genome editing) or large-scale (chromosome silencing) perturbations. After initial validation and in parallel with further methods development, we will apply our new tools to the analysis of three biological systems: we will characterize the dynamics of nuclear architecture during the directed differentiation of naïve human ESCs into cardiomyocytes and endothelial cells; we will test the hypothesis that cardiomyopathy-inducing mutations in the nuclear scaffolding protein, lamin A, are associated with derangements in cardiomyocyte nuclear architecture; and we will determine the changes in human cardiomyocyte nuclear architecture induced by trisomy 21. The proposed center will produce new experimental protocols for ascertaining 4D nucleome architecture, two new software toolkits for modeling the 4D nucleome and linking features of the nucleome to other types of genomic data, a variety of publicly available, large-scale 4D nucleome data sets in mouse and human systems, and fundamental insights into human biology and disease. In all of this work, we will work closely and openly with NOFIC and the 4DN Network to maximize the impact of our center and the overall program.

 描述：当前的基因组学挑战涉及在所有相关尺度上准确地断言DNA在体内的3D构象，然后将会议变化与动态过程（例如细胞周期，分化和疾病）联系起来。在这里，我们建议建立华盛顿大学的核组织与功能中心，汇集一个研究人员的跨学科团队，其专业知识的潜水领域 - 技术开发，计算建模以及鼠标和人类生物学 - 使它们非常适合这一挑战。我们的总体假设是，随着时间的流逝，基因组结构的变化（4D核）将导致对人类生物学和疾病的基本见解。我们将通过开发实验和计算方法开发的结合，再加上其系统的生物学验证以及对发展和疾病与疾病相关的系统的应用，以解决这一假设。在实验方面，我们将进一步优化我们最近开发的DNase Hi-C测定法，包括单个细胞的组合方法，最终旨在同时测定许多单个单元中每个细胞中的核结构和基因表达。在计算方面，我们将扩展现有的3D建模算法，以说明二倍体，细胞间变异性，基因组架构的层次结构性质，并明确地对细胞周期和细胞分化时间尺度进行明确模拟体系结构的变化。然后，我们将采用几种完整的计算方法将我们的4D核模型与现有的1D基因组学数据集联系起来。这些新的实验技术和计算技术的输出将在几种良好理解的模型系统中进行正交验证：人类细胞系，特定F1杂化小鼠的体内组织，小鼠胚胎干细胞（ESC）和骨骼肌细胞。我们还将测试模型的特定预测，以响应靶向（基因组编辑）或大规模（染色体沉默）扰动。在初始验证并与进一步的方法开发并行之后，我们将把新工具应用于对三个生物系统的分析：我们将在人类ESC在人体ESC分化为心肌细胞和内皮细胞中的核结构动力学；我们将检验以下假设：心肌病诱导的核脚手架蛋白A层粘连蛋白A与心肌细胞核结构的进化有关。我们将确定由21 Trisome 21引起的人类心肌细胞核体系结构的变化。拟议的中心将生成新的实验方案，以确定4D核体系结构，这是两个新的软件工具包，用于建模核心的4D核和连接特征和其他类型的基因组数据，以及各种各样的基因组数据，并将各种类型的4D核数据组和人类的人类系统和人类构成。在所有这些工作中，我们将与NOFIC和4DN网络紧密合作，以最大程度地发挥我们的中心和整体计划的影响。

项目成果

Jointly Embedding Multiple Single-Cell Omics Measurements.

• DOI: 10.4230/lipics.wabi.2019.10
• 发表时间: 2019-09-03
• 期刊: Algorithms in bioinformatics : ... International Workshop, WABI ..., proceedings. WABI (Workshop)
• 作者: Liu, Jie;Huang, Yuanhao;Noble, William Stafford
• 通讯作者: Noble, William Stafford

Unsupervised manifold alignment for single-cell multi-omics data.

• DOI: 10.1145/3388440.3412410
• 发表时间: 2020-09
• 期刊: ACM-BCB ... ... : the ... ACM Conference on Bioinformatics, Computational Biology and Biomedicine. ACM Conference on Bioinformatics, Computational Biology and Biomedicine
• 作者: Singh R;Demetci P;Bonora G;Ramani V;Lee C;Fang H;Duan Z;Deng X;Shendure J;Disteche C;Noble WS
• 通讯作者: Noble WS

Single-cell landscape of nuclear configuration and gene expression during stem cell differentiation and X inactivation.

• DOI: 10.1186/s13059-021-02432-w
• 发表时间: 2021-09-27
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Bonora G;Ramani V;Singh R;Fang H;Jackson DL;Srivatsan S;Qiu R;Lee C;Trapnell C;Shendure J;Duan Z;Deng X;Noble WS;Disteche CM
• 通讯作者: Disteche CM

Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome.

• DOI: 10.1038/s41467-020-19879-3
• 发表时间: 2020-11-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Fang H;Bonora G;Lewandowski JP;Thakur J;Filippova GN;Henikoff S;Shendure J;Duan Z;Rinn JL;Deng X;Noble WS;Disteche CM
• 通讯作者: Disteche CM

Targeted DNase Hi-C.

• DOI: 10.1007/978-1-0716-0664-3_5
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Duan Z