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

项目主任/首席研究员（梁、杰）：