Constructing High-Resolution Ensemble Models of 3D Single-Cell Chromatin Conformations of eQTL Loci from Integrated Analysis of 4DN-GTEx Data towards Structural Basis of Differential Gene Expression

从 4DN-GTEx 数据的集成分析构建 eQTL 位点 3D 单细胞染色质构象的高分辨率整体模型，以构建差异基因表达的结构基础

• 批准号: 10357063
• 负责人: Jie Liang
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357063
• 关键词: 3-Dimensional; Accounting; Affect; Algorithms; Biological; Cells; Chromatin; Chromatin Fiber; Chromatin Structure; Data; Data Set; Databases; Elements; Enhancers; Epithelial; Fibroblasts; Frequencies; Funding; Gene Expression; Gene Expression Regulation; Gene Order; Genes; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Health; Heterogeneity; Hi-C; Human; Lymphocyte; Modeling; Molecular Conformation; Muscle Cells; Nature; Nuclear; Pattern; Polymers; Principal Investigator; Quantitative Trait Loci; Resolution; Resources; Role; Structure; Structure-Activity Relationship; Three-dimensional analysis; Tissue-Specific Gene Expression; Tissues; Validation; Variant; Work; base; chromosome conformation capture; comparative; computational pipelines; computerized tools; data resource; differential expression; gene interaction; genetic variant; genome sequencing; genomic locus; improved; insight; novel; programs; promoter; structural genomics; success; three dimensional structure; three-dimensional modeling; tool; transcriptome sequencing; whole genome

Program Director/Principal Investigator (Liang, Jie): PROJECT SUMMARY/ABSTRACT To enhance the utility of the common fund supported 4D Nucleome (4DN) database and Genotype- Tissue Expression (GTEx) database, we will develop novel computational tools for infering the spatial organizations of genomic elements to elucidate how eQTLs can regulate the expression of their target genes. Our tools will integrate 4DN and GTEx data and overcome the limit of the 2D nature of Hi-C frequency heatmaps, enabling construction of large 3D ensembles of high-resolution models of single-cell chromatin conformations for loci containing tissue-specific genetic variants associated with differential expression. By accounting for 3D polymer effects of random collision between genomic elements due to nuclear volume confinement, our tools will identify chromatin interactions that are statistically significant and likely biologically important. With the ensemble model of single-cell 3D chromatin conformations, our tools will further identify participating genes, promoters, enhancers, and other elements, and elucidate how they are physically arranged in space around genetic variants associated differential gene expression, including how units of higher order many-body interaction for gene regulation may form. In addition, our tools will quantify the presence of heterogeneous subpopulation of cells with different chromatin 3D configurations, allowing probabilistic understanding of the heterogeneous physical interactions around eQTLs. With planned comparative analysis of 3D chromatin conformations from different tissues, different spatial pattern of arrangement of genes and elements important for gene expression will be uncovered, resulting better understanding of genome structure and function relationship. Overall, we will demonstrate significant added-power of integrating two important Common Fund data resources and will provide tools to facilitate understanding the relationship between genome topology and gene expression. Our work will enable highly specific and compelling testable hypothesis on mechanisms of gene regulation to be formulated based on the reconstructed 3D spatial genome topology at loci that harbor variants and eGenes. Validation or refutation of these hypotheses will lead to new insight into the relationship of genome structure and genome function important for improving human health. 0925-0001 (Rev. 03/16) Page Continuation Format Page

项目总监/首席调查员(梁杰)： 项目摘要/摘要 为加强共同基金支持的4D核糖体数据库和基因分型的效用- 组织表达(GTEx)数据库，我们将开发新的计算工具来推断空间 基因组元件的组织以阐明eQTL如何调节其靶标的表达 基因。我们的工具将集成4DN和GTEx数据，并克服Hi-C的2D性质的限制 频率热图，支持构建大型3D高分辨率模型集成 含有组织特异性遗传变异的基因座的单细胞染色质构象 差异表达。通过考虑基因组之间随机碰撞的3D聚合物效应 由于核体积受限，我们的工具将识别 在统计学上有重要意义，可能在生物学上也很重要。用单细胞3D的系综模型 染色质构象，我们的工具将进一步确定参与基因、启动子、增强子和 其他元素，并阐明它们是如何在遗传变异周围的空间中物理排列的 相关的差异基因表达，包括单位如何更高阶的多体相互作用 基因调控可能会形成。此外，我们的工具将量化异类的存在 具有不同染色质3D构型的细胞亚群，允许概率理解 EQTL周围的异质物理相互作用。与计划中的3D对比分析 不同组织的染色质构象，不同的基因排列空间模式和 基因表达的重要元素将被发现，从而更好地理解基因组 结构与功能的关系。总体而言，我们将展示显著的附加功能 整合两个重要的共同基金数据资源，并将提供工具以促进 了解基因组拓扑和基因表达之间的关系。我们的工作将使 关于基因调控机制的高度具体和令人信服的可检验假说 基于重构的3D空间基因组拓扑在包含变异和 埃吉尼斯。对这些假说的验证或反驳将导致对 基因组结构和基因组功能对改善人类健康具有重要意义。 0925-0001(03/16版)页面续格式页面