Structural Annotation of the Human Genome

项目总结 细胞必须调节它们的基因组，以便基因在适当的细胞类型中表达，并在 正确的时间。此外，当细胞经历细胞周期时，染色体必须复制、压缩，然后 忠实地实行种族隔离。所有这些过程都需要正确的基因组折叠。折叠中的缺陷，例如 将基因环化到错误的末端增强子，或在有丝分裂过程中错误地压缩染色体，可能会导致 基因在错误的地点和错误的时间表达，或者是基因组不稳定。这类缺陷可能 会导致包括癌症在内的疾病。在确定折叠原理方面已经取得了巨大的进展 染色体，折叠如何在细胞周期中变化，顺式元件在折叠染色体中的作用以及 长程基因调控，以及折叠染色体的分子机器和机制。在……里面 间期染色体折叠成拓扑相关的结构域和粘附素介导的环。 染色体也通过一个阶段分割形成活性和非活性染色质结构域 分离过程。在有丝分裂中，染色体重新折叠成凝集素介导的线性压缩阵列 循环。我们和其他人证明了凝集素介导的环路形成和凝聚素介导的交替 环的形成驱动细胞周期阶段相关的染色体折叠。然而，有三个关键方面 染色体的组织在很大程度上仍未被探索，主要是由于缺乏实验方法。 首先，人们对调节姐妹染色单体间相互作用的顺式元件的特性知之甚少。 这些相互作用对于忠实的染色体分离是至关重要的。第二，网络的拓扑状态 染色体，即染色体内和染色体间连接的存在，几乎完全没有被研究过。 在复制和转录过程中形成连接，这对正确的基因表达造成了障碍 和染色体分离，因此细胞必须不断地解决这些问题。顺式要素和反式 控制基因组拓扑状态的因素在很大程度上是未知的。第三，因素 而驱动染色体区划的顺式元件的特征也很差。我们最近开发了 三种新的基因组技术，SisterC，多接触3C和液体染色质Hi-C，可以进行研究 这三个悬而未决的问题分别是。在这里，我们将使用这些方法来识别 控制染色体区划、连锁的基因组DNA元件及其作用方式 它们在解开和分离姐妹染色单体方面起到了作用。

PROJECT SUMMARY Cells must regulate their genome so that genes are expressed in the appropriate cell type, and at the correct time. Further, as cells go through the cell cycle chromosomes must be replicated, compacted and then faithfully segregated. All these processes require correct folding of the genome. Defects in folding, e.g., the looping of genes to incorrect distal enhancers, or incorrect chromosome compaction during mitosis, can lead to genes being expressed in the wrong place and at the wrong time, or to genome instability. Such defects can lead to diseases including cancer. There has been tremendous progress in identifying folding principles of chromosomes, how folding changes during the cell cycle, roles of cis elements in folding chromosomes and long-range gene regulation, and the molecular machines and mechanisms that fold chromosomes. In interphase chromosomes fold into topologically associating domains and cohesin-mediated loops. Chromosomes also compartmentalize to form active and inactive chromatin domains through a phase separation process. In mitosis, chromosomes refold into linearly compressed arrays of condensin-mediated loops. We and others showed that alternation of cohesin-mediated loop formation and condensin-mediated loop formation drives cell cycle stage-dependent chromosome folding. However, three critical aspects of chromosome organization have remained largely unexplored, mostly due to lack of experimental approaches. First, little is known about the identity of cis elements that mediate interactions between sister chromatids, yet these interactions are critical for faithful chromosome segregation. Second, the topological state of chromosomes, i.e., the presence of intra- and inter-chromosomal catenations is almost entirely unexplored. Catenations form during replication and transcription and these create impediments to correct gene expression and chromosome segregation and therefore the cell must constantly resolve these. Cis elements and trans factors involved in controlling the topological state of the genome are largely uncharacterized. Third, factors and cis elements driving chromosome compartmentalization are poorly characterized. We recently developed three new genomic technologies, SisterC, Multi-Contact 3C, and Liquid Chromatin Hi-C that allow studying each of these three outstanding questions respectively. Here, we will employ these methods to identify genomic DNA elements, and their mode of action, that control chromosome compartmentalization, catenation and decatenation, and that play roles in disentangling and segregating sister chromatids.