Structural Annotation of the Human Genome

描述（由申请人提供）：基因组执行若干关键任务，以确保正常发育、体内平衡和健康。首先，基因转录需要精确调控，基因调控缺陷会导致癌症、糖尿病等人类疾病。其次，染色体需要复制，然后准确可靠地传递给子细胞。染色体分离需要广泛的染色体压实。这个过程中的缺陷会导致基因组不稳定、非整倍体和癌症。近年来的研究表明，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。这里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染色体的三维（3D）排列，这将允许识别参与染色体三维折叠的顺式元件。一套新的和强大的基因组技术（5C和Hi-C），允许三维染色体折叠的绘图将应用于人类基因组的研究。这些技术将与同步细胞群的使用和调控元件的全基因组分析相结合，以表征细胞周期中不同的染色体构象，并确定所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三维折叠的过程，如DNA拓扑结构的转录和调节。该项目将为长期存在的问题提供答案，这些问题涉及远程基因调控、染色体分离、转录谱向子细胞的表观遗传传递，以及致密中期染色体形成的过程，这些问题在很大程度上仍然是神秘的。

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.