Structural Annotation of the Human Genome

描述(由申请人提供)：基因组执行几个关键任务，以确保正常发育、内稳态和健康。首先，基因转录需要精确调控，基因调控缺陷可能会导致癌症和糖尿病等人类疾病。其次，需要复制染色体，然后准确可靠地将其传递给子细胞。染色体分离需要广泛的染色体紧凑。这一过程中的缺陷可能导致基因组不稳定、非整倍体和癌症。最近的研究表明，染色体的空间组织是控制基因表达和染色体分离的主要因素。本文提出的工作将首次以前所未有的分辨率表征细胞周期不同阶段的染色体的三维(3D)排列，这将使识别参与染色体3D折叠的顺式元件成为可能。一套新颖而强大的基因组技术(5C和Hi-C)将被应用于人类基因组的研究，这些技术允许绘制3D染色体折叠图。这些技术将与同步细胞群体和全基因组调控元件分析相结合，以确定细胞周期中不同的染色体构象，并识别涉及的顺式元件和一些反式因子。此外，还将研究决定基因组3D折叠的过程，如DNA拓扑的转录和调节。这个项目将为长期存在的问题提供答案，这些问题涉及长程基因调控、染色体分离、转录谱向子细胞的表观遗传传递，以及在很大程度上仍然神秘的致密中期染色体的形成过程。 与公共卫生相关：人类基因组包含人类正常发育所需的所有遗传信息。活细胞内基因组的三维(3D)组织正在成为控制基因组的关键决定因素，而3D基因组组织的缺陷可能导致人类疾病，如癌症和糖尿病。这项提议旨在确定染色体的3D折叠，以及这种折叠与人类基因组的适当调节有何关系。

DESCRIPTION (provided by applicant): Genomes perform several critical tasks to ensure normal development, homeostasis and health. First, gene transcription needs to be accurately regulated and defects in gene regulation can result in human diseases such as cancer and diabetes. Second, chromosomes need to be replicated and then accurately and reliably transmitted to daughter cells. Chromosome segregation requires extensive chromosome compaction. Defects in this process can lead to genome instability, aneuploidy and cancer. Recent studies have revealed that the spatial organization of chromosomes is a major factor in controlling both gene expression and chromosome segregation. The work proposed here will for the first time characterize the three-dimensional (3D) arrangement of chromosomes during different stages of the cell cycle at unprecedented resolution which will allow the identification of cis-elements involved in the 3D folding of chromosomes. A set of novel and powerful genomic technologies (5C and Hi-C) that allow the mapping of 3D chromosome folding will be applied to the study of the human genome. These technologies will be combined with the use of synchronous cell populations and genome-wide analysis of regulatory elements to characterize the different chromosome conformations during the cell cycle and to identify the cis-elements and some trans-factors involved. In addition, the processes that determine 3D folding of the genome, such as transcription and modulation of DNA topology will be studied. This project will provide answers to long-standing questions related to long-range gene regulation, chromosome segregation, the epigenetic transmission of transcription profiles to daughter cells, and the still largely mysterious process of formation of compact metaphase chromosomes. PUBLIC HEALTH RELEVANCE: The human genome contains all genetic information required for normal human development. The three- dimensional (3D) organization of the genome inside living cells is emerging as a critical determinant of controlling the genome, and defects in 3D genome organization can lead to human diseases such as cancer and diabetes. This proposal aims to determine the 3D folding of chromosomes and how that folding is related to the appropriate regulation of the human genome.