Structural Annotation of the Human Genome

描述（申请人提供）：染色体的空间组织在调控基因表达和维持基因组稳定性方面起着重要作用。染色体空间排列的详细知识将有助于阐明调节人类基因组的分子机制，并将为人类疾病的遗传基础提供见解。我们已经开发了强大的分子和基因组技术来探测染色体的三维结构。这些方法允许通过广泛分离的功能元件（如启动子和增强子）之间的远程染色体相互作用的综合分析染色体折叠。我们将这些技术应用于细胞分裂过程中的人类细胞，发现染色体可以组织成两种基本不同的三维结构：在间期细胞中观察到的一种结构由不同类型的染色体结构域和染色质环组成。这个结构专门用于基因调控。在有丝分裂细胞中观察到第二种结构，当染色体为细胞分裂而浓缩时。我们发现这种结构最好描述为连续染色质环的线性组织纵向压缩阵列。在这里，我们建议首先更详细地研究这两种不同的染色体构象，然后研究细胞用于构建每种结构的基因组元件和机制。我们提出的研究将导致深入了解更精细的染色体组织和连接间期和有丝分裂染色体结构的复杂折叠途径。

DESCRIPTION (provided by applicant): The spatial organization of chromosomes plays important roles in regulation of gene expression and maintenance of genome stability. Detailed knowledge of the spatial arrangements of chromosomes will help elucidate the molecular mechanisms that regulate the human genome, and will provide insights into the genetic basis of human disease. We have developed powerful molecular and genomic technologies to probe the three-dimensional structure of chromosomes. These methods allow the analysis of chromosome folding through the comprehensive analysis of long-range chromosomal interactions between widely separated functional elements, such as promoters and enhancers. We have applied these technologies to human cells during cell division and discovered that chromosomes can be organized in two fundamentally distinct three- dimensional structures: one structure, observed in interphase cells, is composed of a hierarchy of different types of chromosomal domains and chromatin loops. This structure is dedicated to gene regulation. A second structure is observed in mitotic cells, when chromosomes become condensed in preparation of cell division. We discovered that this structure is best described as a linearly organized longitudinally compressed array of consecutive chromatin loops. Here we propose to first study these two distinct chromosome conformations in more detail, and then to study the genomic elements and mechanisms cells employ to build each structure. Our proposed studies will lead to insights into the finer-scale organization of chromosomes and the intricate folding pathways that connect interphase and mitotic chromosome structures.