Mechanisms integrating lineage history with fate specification in C. elegans

线虫谱系历史与命运规范相结合的机制

• 批准号: 8730688
• 负责人: John Isaac Murray
• 金额: $ 29.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730688
• 关键词: Animals; Anterior; Architecture; Behavior; Binding; Binding Sites; Biological Assay; Caenorhabditis elegans; Cell Fate Control; Cells; ChIP-seq; Data Set; Development; Disease; Ectoderm Cell; Elements; Embryo; Embryonic Development; Enhancers; Environment; Event; Gene Expression Regulation; Genes; Health; Human; Individual; Invertebrates; Light; Logic; Malignant Neoplasms; Maps; Measures; Mesoderm Cell; Methods; Modeling; Molecular Profiling; Mutagenesis; Mutation; Nuclear; Organism; Orthologous Gene; Pathway interactions; Pattern; Phenotype; Play; Process; Recording of previous events; Reporter; Resolution; Role; Signal Pathway; Signal Transduction; Spottings; Stereotyping; System; Testing; Tissue-Specific Gene Expression; Translating; base; cell type; genome-wide; innovation; mutant; promoter; tool; transcription factor; tumorigenesis; zygote

DESCRIPTION (provided by applicant): Context-dependent transcription factors play a critical role in defining which genes are regulated during development and disease, allowing the same factors to play different roles in different cells. The C. elegans embryo is an deal system for a comprehensive study of the role of lineage history in the context-dependent regulation of cell fate because of its invariant lineage and powerful experimental tools. We recently developed automated lineage tracing and expression mapping methods for C. elegans embryogenesis and measured the expression of over 127 fluorescent reporters for transcription factor (TF) expression in every cell of developing embryos. From this dataset, we identified over 30 TFs whose expression correlates directly with both lineage identity and Wnt signaling but not with terminal fate. In Aim 1, we will apply our lineage tracing methods to elucidate how context factors determine differential cellular respones to Wnt signaling, a key cell fate regulator and driver of oncogenesis. We will do this by assaying binding of the Wnt effector POP-1 to candidate targets, genome-wide mapping of POP-1 binding and detailed cis-regulatory analysis. In Aim 2, we will determine the function of TFs with lineage-specific expression by high-resolution phenotyping and genome-wide expression profiling of mutants. These studies will define mechanisms by which lineage identity is translated into cell fate and shed light on context-dependent differences in TF and Wnt targets in C. elegans and other organisms.

描述（由申请人提供）：上下文依赖性转录因子在确定发育和疾病过程中哪些基因受到调控方面起着关键作用，允许相同的因子在不同的细胞中发挥不同的作用。秀丽隐杆线虫胚胎由于其不变的谱系和强大的实验工具，是一个全面研究谱系历史在细胞命运的环境依赖性调节中的作用的交易系统。我们最近开发了秀丽隐杆线虫胚胎发生的自动谱系追踪和表达定位方法，并在发育胚胎的每个细胞中测量了超过127个转录因子（TF）荧光报告基因的表达。从这个数据集中，我们确定了超过30个tf，其表达与谱系身份和Wnt信号直接相关，但与终末期命运无关。在Aim 1中，我们将应用我们的谱系追踪方法来阐明环境因素如何决定细胞对关键细胞Wnt信号的差异反应