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)：上下文相关的转录因子在确定哪些基因在发育和疾病期间受到调控方面发挥了关键作用，允许相同的因子在不同的细胞中发挥不同的作用。线虫胚胎是一种处理系统，用于全面研究谱系历史在细胞命运调控中的作用，因为它具有不变的谱系和强大的实验工具。我们最近开发了用于线虫胚胎发生的自动化谱系追踪和表达图谱方法，并测量了127多个转录因子(TF)在发育中的胚胎每个细胞中的表达。从这个数据集中，我们识别了30多个转录因子，它们的表达与血统认同和Wnt信号直接相关，但与终端命运无关。在目标1中，我们将应用我们的谱系追踪方法来阐明背景因素如何决定细胞对Wnt信号的不同反应，Wnt信号是一个关键细胞 命运的调节者和肿瘤发生的驱动力。我们将通过分析WNT效应器POP-1与候选靶点的结合、POP-1结合的全基因组图谱和详细的顺式调控分析来做到这一点。在目标2中，我们将通过突变的高分辨率表型和全基因组表达谱来确定具有谱系特异性表达的转录因子的功能。这些研究将确定谱系认同转化为细胞命运的机制，并阐明线虫和其他生物中Tf和Wnt靶标的上下文相关差异。