Regulation of chromosome structure and gene expression by architectural proteins

项目摘要 细胞核内DNA的空间组织对于适当的基因表达和细胞增殖至关重要。 功能基因组折叠的模式可以因细胞类型而异，并且在人类疾病中受到干扰， 发育综合征和癌症。控制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。 一系列的结构将基因组的拓扑结构和活动联系起来。基因控制的关键结构是 将基因及其调控元件紧密结合在一起的染色质环。基因组- 广泛的分析表明，每个基因都有10多个调控元件，但对这些调控元件知之甚少。 调控元件如何找到它们的靶基因或它们如何在分子水平上发挥作用。一个主要的目标， 该领域的目标是识别基因组中的所有DNA环，并确定它们如何单独作用， 组合以调节基因表达。 染色体结构维持（SMC）复合物是一个蛋白质家族， 塑造基因组的三维结构。两种主要的SMC复合物，粘附素和 凝聚素，首先被确定为它们在细胞周期中的染色体重组中的作用。最近 工作暗示这些因素在基因调控间期，并假设这些环- 成形的蛋白质复合物通过促进DNA中的环而起作用。重要的是要揭示的机制， 确定在何处以及如何与基因组相互作用的凝聚素和功能的后果 这些环结构的发展和疾病的过程。 这项研究计划的长期范围是从基因组的线性视图移动到全景 基因组在三维空间中的物理方向指导基因表达的视图。这 该项目将侧重于三个主要问题。首先，每种结构蛋白质对整体结构的贡献是什么？ 基因组的拓扑结构第二，在DNA循环和基因表达过程中， 监管？第三，DNA环如何影响基因活性？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， 特定的突变结构蛋白。这项研究将有助于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.