Role of Nucleolus and Ribosome Biogenesis in Coordinating Organism-wide Growth

我的研究计划的首要任务是阐明核糖体DNA(RDNA)基因座和 核糖体生物发生与细胞过程相连，以协调生物体过程中复杂的生长模式 发展。本提案的总体目标是：(1)确定细胞非自主因素 提供核糖体合成检查点以控制整个生物体的生长和(2)对 核仁在生物体发育过程中的表观遗传功能。首先，我们将确定细胞非调控因子 在线虫中，通过密集的正向遗传筛选来阻止线虫的自主生长，这些菌株既产生野生的 精确谱系中的类型和纯合的核糖体蛋白和rDNA零细胞。了解组织特异性 为了对整个生物体的生长做出贡献，我们将优化一个能够可逆地阻止新核糖体的系统 以组织和特定阶段的方式进行合成。第二，我们将利用可存活的线虫胚胎 缺乏多拷贝rDNA基因座(因此是核仁结构)来研究核仁在 基因组组织和基因表达。我们将识别和验证核仁相关结构域。我们会 然后确定核仁对染色体结构、基因组组织和基因的全球影响 表情。这项研究将(1)阐明调节整个生物体的细胞非自主途径 生长协调和(2)将确定核仁的表观遗传作用，这些作用与其本质不同 核糖体生物发生功能。

The overarching mission of my research program is to elucidate how the ribosomal DNA (rDNA) locus and ribosome biogenesis connect to cellular processes to coordinate complex growth modes during organismal development. The overall objectives of the current proposal are: (1) identification of cell non-autonomous factors that provide a ribosome synthesis checkpoint to control organism-wide growth and (2) investigation of the epigenetic function of nucleolus during organism development. First, we will identify regulators of cell non- autonomous growth arrest in C. elegans by intensive forward genetic screens in strains that produce both wild- type and homozygous ribosomal protein & rDNA null cells in precise lineages. To understand tissue specific contributions to organism-wide growth, we will optimize a system that will reversibly block new ribosome synthesis in a tissue and stage-specific way. Second, we will take advantage of viable C. elegans embryos that lack multi-copy rDNA locus (hence the nucleolus structure) to investigate the fundamental roles of nucleolus in genome organization and gene expression. We will identify and validate nucleolus associated domains. We will then identify the global impact of nucleolus on chromosome architecture, genome organization and gene expression. This study will (1) shed light onto the cell non-autonomous pathways that regulate organism-wide growth coordination and (2) will identify the epigenetic roles of the nucleolus that are distinct from its essential ribosome biogenesis function.