Regulation of chromosome structure and gene expression by architectural proteins

项目概要 细胞核内 DNA 的空间组织对于正确的基因表达和细胞生长至关重要。 功能。基因组折叠模式可能因细胞类型而异，并且在人类疾病中受到干扰，例如 发育综合症和癌症。控制基因组组织的分子机制是 人们对其知之甚少，但对人类健康至关重要。 结构层次将基因组拓扑和活动联系起来。基因控制的关键结构是 染色质环将基因及其调控元件紧密地物理连接在一起。基因组- 广泛的分析表明每个基因都有超过 10 个调控元件，但人们对其知之甚少 调控元件如何找到其靶基因或它们如何在分子水平上发挥作用。的一个主要目标是 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发挥作用。 组合来调节基因表达。 染色体结构维持 (SMC) 复合物是一个蛋白质家族，在 塑造基因组的三维结构。两个主要的 SMC 复合物，Cohesin 和 凝缩蛋白最初因其在细胞周期期间染色体重组中的作用而被鉴定。最近 工作已经将这些因素与间期的基因调控联系起来，并且假设这些环 形状蛋白复合物通过促进 DNA 中的环发挥作用。揭示其中的机制很重要 确定 Cohesin 和 Condensin 在何处以及如何与基因组相互作用以及功能后果 这些循环结构对发育和疾病过程的影响。 该研究计划的长期范围是将基因组的线性视图转变为全景视图 查看三维空间中基因组的物理方向指导基因表达的位置。这个 项目将重点解决三个主要问题。首先，每种结构蛋白对整体有什么贡献 基因组的拓扑结构？其次，结构蛋白在 DNA 循环和基因表达过程中是如何调节的？ 监管？第三，DNA环如何影响基因活性？这些研究将评估生化和 控制基因表达和 DNA 循环并决定其后果的分子过程 特定的突变结构蛋白。这项研究将揭示调控元件如何控制基因组 组织、指导基因表达并定义发育过程中的细胞类型。

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.