GLOBAL GENE REGULATORY NETWORKS FOR SPECIFIC CELL TYPES OF THE SEA URCHIN EMBRYO

海胆胚胎特定细胞类型的全球基因调控网络

• 批准号: 8288724
• 负责人: ERIC H DAVIDSON
• 金额: $ 58.13万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288724
• 关键词: Adult; Animals; Bioinformatics; Biological Models; Biological Process; Cell Lineage; Cell physiology; Cells; Cellular biology; Clinical; Code; Complementary DNA; Complex; Conserved Sequence; Development; Developmental Gene; Disease; Effector Cell; Embryo; Endoderm; Endoderm Cell; Excision; Fluorochrome; Gene Expression; Gene Expression Profile; Genes; Genomics; Immune; Instruction; Intergenic Sequence; Knock-in Mouse; Knowledge; Learning; Life; Link; Measurement; Mediating; Mesoderm; Methods; Morphogenesis; Natural Immunity; Oral; Pattern Formation; Physiological; Population; Primitive foregut structure; Problem Solving; Procedures; Process; Proteins; Proxen; Recovery; Regulator Genes; Research; Sea Urchins; Sequence Analysis; Signaling Molecule; Site; Solid; Solutions; Staging; Structure; System; Technology; Time; To specify; Validation; Work; abstracting; blastomere structure; cell type; egg; embryo cell; gastrulation; genome sequencing; interest; network models; research study; success; transcription factor

GLOBAL GENE REGULATORY NETWORKS FOR SPECIFIC CELL TYPES OF THE SEA URCHIN EMBRYO ABSTRACT All developmental, morphogenetic, and differentiation functions of animal cells are executed by large, specifically deployed batteries and cassettes of downstream protein coding genes. A major success of bioscience in recent years has been system level elucidation of the upstream gene regulatory networks (GRNs) that control pattern formation and determine development of the body plan. GRNs consist of genes encoding transcription factors and signaling molecules, plus the transcriptional linkages among these genes, and they determine the regulatory state of every cell at every point in developmental time. Therefore they include the control inputs into all the downstream genes that do the work of the cell. But an enormously important gap in understanding now separates the upstream GRNs that we are beginning to learn about from the downstream effectors of cell function: What is the actual control circuitry that determines the deployment of these downstream genes? How, exactly, are GRNs causally connected to cellular functions of differentiation and morphogenesis? In principle, given knowledge of the upstream GRN and various newly available technology, this gap can be closed, and the problem solved at a system level, and this is the particular object of the present proposal. We will choose three cell types of the developing sea urchin embryo, each of general interest. Knowledge of the upstream GRNs of this embryo is more advanced than for any other system. The target cell types are the immune cells of the embryo, where the downstream effector genes encode a great variety of innate immunity proteins; gastrulating endoderm cells, where the downstream genes mediate gastrular invagination; and the totipotent set-aside cells of the embryonic coelomic pouches that in larval stage produce the adult body plan, where the downstream effector cells include those that maintain totipotency. Innate immunity, gastrular invagination, and totipotent cell lineages are all pan-bilaterian features. The approach, briefly, will be isolation of each cell type using specific regulatory gene expression and FACS; deep transcriptome sequencing; bioinformatic prediction; and validation of causal regulatory connections to specifically expressed genes by high throughput cis- regulatory analysis. This project will provide the first global upstream-downstream GRN for any developing system. It will inform as to basic principles by which downstream gene cassettes are organized. It will also serve as a technological demonstration project for similar approaches to mammalian systems.

针对特定海洋细胞类型的全球基因调控网络 海胆胚胎 摘要 动物细胞的所有发育、形态发生和分化功能都是由大的、 专门部署了下游蛋白质编码基因的电池和盒式磁带。取得了重大的成功 近年来，生物科学已经在系统水平上阐明了上游基因调控网络 (GRN)控制图案形成并确定车身计划的发展。GRN由基因组成 编码转录因子和信号分子，以及它们之间的转录联系 基因，它们决定了每个细胞在发育时间的每一个时间点的调节状态。因此 它们包括参与细胞工作的所有下游基因的控制输入。但是一个巨大的 认识上的重要差距现在将我们开始了解的上游GRN分开 从细胞功能的下游效应器：决定细胞功能的实际控制电路是什么 这些下游基因的部署？GRN究竟是如何与细胞功能产生因果关系的？ 分化和形态发生的关系？原则上，考虑到上游GRN和各种 最新可用的技术，这个差距是可以弥合的，问题是在系统层面上解决的，这就是 本提案的具体目的。我们将选择发育中的海胆的三种细胞类型 胚胎，每个人都有普遍的兴趣。对胚胎上游GRN的了解比 适用于任何其他系统。目标细胞类型是胚胎的免疫细胞，其中下游的 效应器基因编码多种天然免疫蛋白；原肠形成的内胚层细胞，在那里 下游基因介导胃肠内陷；胚胎的全能预留细胞 在幼虫阶段产生成体计划的体腔袋，在那里下游的效应细胞 包括那些保持全能性的人。先天免疫、胃肠内陷和全能细胞谱系 都是泛双边的特征。简而言之，该方法将使用特定的方法分离每种细胞类型 调控基因表达和流式细胞仪；深层转录组测序；生物信息学预测；以及 高通量顺式作用于特定表达基因的因果调控连接的验证 监管分析。该项目将为任何正在开发的项目提供第一个全球上下游GRN 系统。它将告知组织下游基因盒的基本原则。它还将 作为对哺乳动物系统采取类似方法的技术示范项目。