Regulation of chromosome structure and gene expression by architectural proteins

项目总结 DNA在细胞核内的空间组织对于适当的基因表达和细胞是至关重要的 功能。基因组折叠的模式会因细胞类型而异，在人类疾病中会受到干扰，例如 发育综合征和癌症。支配基因组组织的分子机制是 人们对此知之甚少，但对人类健康至关重要。 一个层次结构将基因组的拓扑结构和活性联系在一起。基因控制的关键结构是 染色质环将基因及其调控元件聚集在一起，物理上非常接近。基因组- 广泛的图谱显示，每个基因都有10多个调控元件，但人们对此知之甚少 调控元件如何找到它们的目标基因，或者它们如何在分子水平上发挥作用。中国的一个主要目标 FIELD的目的是识别基因组中的所有DNA环，并确定它们如何单独和在 联合起来调控基因表达。 染色体结构维持(SMC)复合体是一类蛋白质家族，在细胞周期中起关键作用。 塑造基因组的三维结构。两种主要的SMC复合体，粘附素和 凝集素，首先被确定在细胞周期中的染色体重组中的作用。近期 研究表明，这些因素参与了间期的基因调控，并假设这些环- 成形的蛋白质复合体通过促进DNA中的环起作用。重要的是要揭示 确定粘附素和凝聚素在哪里以及如何与基因组和功能结果相互作用 这些环结构与发育和疾病过程有关。 这一研究计划的长期范围是从基因组的线性视角转向全景 观察基因组在三维空间中的物理方向对基因表达的影响。这 该项目将重点解决三个主要问题。首先，每种建筑蛋白质对整体有什么贡献？ 基因组的拓扑学？第二，建筑蛋白在DNA环路和基因中是如何调节的 监管？第三，DNA环是如何影响基因活性的？这些研究将评估生物化学和 控制基因表达和DNA循环的分子过程，并决定 特定的突变结构蛋白。这项研究将阐明调控元件如何控制基因组 组织，指导基因表达，并在发育过程中定义细胞类型。

PROJECT SUMMARY The spatial organization of DNA within the nucleus is critical for proper gene expression and cellular function. Patterns of genome folding can vary by cell type and are perturbed in human diseases such as developmental syndromes and cancers. The molecular mechanisms that govern genome organization are poorly understood and yet are critically important for human health. A hierarchy of structures link genome topology and activity. Critical structures for gene control are the chromatin loops that bring genes and their regulatory elements together in close physical proximity. Genome- wide profiling indicates that there are more than 10 regulatory elements for every gene, yet little is known about how regulatory elements find their target genes or how they function at the molecular level. A major goal in the field is to identify all of the DNA loops in the genome and determine how they act individually and in combination to regulate gene expression. The Structural Maintenance of Chromosome (SMC) complexes are a family of proteins that play key roles in shaping the three-dimensional architecture of the genome. The two major SMC complexes, Cohesin and Condensin, were first identified for their roles in chromosome re-organization during the cell cycle. Recent work has implicated these factors in gene regulation during interphase, and the assumption is that these ring- shaped protein complexes act by facilitating loops in DNA. It is important to uncover the mechanisms that determine where and how Cohesin and Condensin interact with the genome and the functional consequences of these loop structures to development and disease processes. The long-term scope of this research program is to move from a linear view of the genome to a panoramic view where the physical orientation of the genome in three-dimensional space directs gene expression. This project will focus on three major questions. First, what does each architectural protein contribute to the overall topology of the genome? Second, how are architectural proteins regulated during DNA looping and gene regulation? Third, how do DNA loops impact gene activity? These studies will assess the biochemical and molecular processes that control gene expression and DNA looping and determine the consequences of specific mutant architectural proteins. This research will shed light on how regulatory elements control genome organization, direct gene expression, and define cell types during development.