Constructing Ensembles of 3D Structures of Igh Locus and Predicting Novel Chromosomal Interactions

构建 Igh 基因座 3D 结构的集合并预测新的染色体相互作用

• 批准号: 9317936
• 负责人: Jie Liang
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317936
• 关键词: Alpha Cell; Antigen Receptors; B-Cell Development; B-Lymphocytes; Biological; Biology; Carbon; Cell Nucleus; Cells; Chromatin; Chromatin Loop; Chromatin Modeling; Chromatin Structure; Chromosomes; Computing Methodologies; Contracts; DNA; Data; Development; Distant; Elements; Embryo; Event; Fibroblasts; Formaldehyde; Funding; Generations; Genes; Genome; Genomics; Heavy-Chain Immunoglobulins; IGH@ gene cluster; Immune response; Immunobiology; Immunoglobulin Genes; Infant; Knock-out; Knowledge; Measurement; Measures; Methods; Modeling; Molecular Conformation; Molecular Genetics; Mus; Nuclear; Outcome; Pattern; Polymers; Population; Procedures; Process; Property; Resolution; Sampling; Specific qualifier value; Structural Models; Synapses; System; Techniques; Testing; Three-dimensional analysis; V(D)J Recombination; Work; adaptive immune response; base; chromosome conformation capture; comparative; computerized tools; genetic approach; genetic element; immunoglobulin structure; improved; novel; novel strategies; predictive modeling; restraint; sample fixation; three dimensional structure; three-dimensional modeling

Project Summary/Abstract A central problem of immunobiology is to understand the adaptive immune response. The contraction process of the immunoglobulin heavy chain (Igh) locus is essential for subsequent VDJ joining event to generate antigen receptor diversity. To gain mechanistic understanding of this contraction process, we propose to develop novel computational methods to study spatial structures of the Igh locus before and after contraction. We will generate detailed 3D structural ensembles of chromatin chains of the locus based on looping interactions obtained from chromosome conformation capture carbon copy (5C) studies of the mouse embryonic fibroblast (MEF) cells and the primary pro-B (pro-B) lymphocytes. These 3D models of chromatin chains will satisfy fundamental polymer properties of self-avoidance and nuclear confinement, will account for interactions derived from 5C studies, and can represent the population and possible heterogeneous subpopulations of the Igh locus. In addition, we will specify structural features defining the contraction process and identify critical genomic interactions. Our specific aims are to (1) develop a computational method to generate large ensembles of 1056 3D chromatin chains of the Igh locus representative of cell populations and sub- populations before and after the locus contraction. We will first develop a spatially confined random self-avoiding polymer model to exclude non-specific 3D looping interactions from 5C measurements. We will then develop a method to generate large ensembles of chromatin chains satisfying 5C-derived interactions that can represent the population and sub-populations of cells. We will then (2) specify common as well as differential 3D interaction patterns of genomic elements before and after con- traction, and identify critical 3D genomic interactions through computational knock-out studies. The outcome of our work will be a detailed structural picture of the spatial organization of the Igh locus during contraction, as well as a set of powerful computational tools for building 3D chromatin structures that can be applied to any genomic locus. 3

项目摘要/摘要 免疫生物学的一个核心问题是了解适应性免疫响应。收缩 免疫球蛋白重链（IGH）基因座的过程对于随后的VDJ加入活动至关重要 为了获得对这种收缩过程的机械理解， 我们建议开发新的计算方法，以研究IGH基因座的空间结构 并在收缩后。我们将生成染色质链的详细的3D结构集合 基于从染色体会议捕获碳副本获得的循环相互作用的基因座 （5C）对小鼠胚胎纤维细胞（MEF）细胞和主要pro-B（pro-B）淋巴细胞的研究。 这些染色质链的3D模型将满足自避免的基本聚合物特性 和核定核，将解释从5C研究中得出的相互作用，并可以代表 IGH基因座的种群和可能的异质亚群。此外，我们将指定 结构特征定义了收缩过程并确定关键的基因组相互作用。 我们的特定目的是（1）开发一种计算方法来生成大合奏 IGH基因座的1056 3D染色质链，代表细胞种群和亚 基因座收缩之前和之后的种群。我们将首先开发出空间构建的随机 从5C测量值中排除非特定3D循环相互作用的自避免的聚合物模型。 然后，我们将开发一种生成满足5C衍生的染色质链的大合同的方法 可以代表细胞的种群和亚群的相互作用。然后，我们将（2）指定 共同的基因组元素的常见和差异3D相互作用模式 通过计算敲除研究来识别关键的3D基因组相互作用。这 我们工作的结果将是IGH基因座空间组织的详细结构图。 在收缩期间，以及一组强大的计算工具，用于构建3D染色质结构 可以应用于任何基因组基因座。 3