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）：与上下文有关的转录因子在定义哪些基因在发育和疾病期间的调节中起关键作用，从而使相同的因素在不同细胞中起着不同的作用。 秀丽隐杆线虫的胚胎是一种交易系统，用于全面研究谱系历史在上下文依赖细胞命运的调节中的作用，因为其不变谱系和强大的实验工具。我们最近开发了用于秀丽隐杆线虫胚胎发生的自动谱系跟踪和表达映射方法，并测量了在发育胚胎的每个细胞中的转录因子（TF）表达超过127个荧光记者的表达。从该数据集中，我们确定了超过30个TF，其表达式与谱系身份和Wnt信号直接相关，但与终端命运无关。 在AIM 1中，我们将应用我们的谱系追踪方法来阐明上下文因素如何确定对Wnt信号的差异细胞呼吸，一个钥匙单元 命运调节因子和肿瘤发生的驱动力。 我们将通过分析Wnt效应子POP-1与候选靶标的结合，POP-1结合的全基因组映射和详细的顺式调节分析来做到这一点。 在AIM 2中，我们将通过高分辨率表型和突变体的全基因组表达分析来确定具有谱系特异性表达的TF的功能。这些研究将定义谱系身份转化为细胞命运的机制，并阐明了秀丽隐杆线虫和其他生物中TF和WNT靶标的上下文依赖性差异。