Mechanisms integrating lineage history with fate specification in C. elegans

描述（由申请人提供）：背景依赖性转录因子在确定发育和疾病期间哪些基因受到调控方面发挥关键作用，允许相同的因子在不同的细胞中发挥不同的作用。 梭 线虫胚胎是一个理想的系统，因为它的谱系不变和强大的实验工具，用于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。我们最近开发了C. elegans胚胎发生，并测量了超过127个用于转录因子（TF）表达的荧光报告基因在发育胚胎的每个细胞中的表达。从该数据集中，我们鉴定了超过30种TF，其表达与谱系身份和Wnt信号传导直接相关，但与最终命运无关。 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对Wnt信号传导的不同细胞反应，这是一个关键细胞， 肿瘤发生的命运调节和驱动。 我们将通过分析Wnt效应子POP-1与候选靶点的结合、POP-1结合的全基因组定位和详细的顺式调控分析来实现这一点。 在目标2中，我们将通过突变体的高分辨率表型分析和全基因组表达谱分析来确定具有谱系特异性表达的TF的功能。这些研究将确定谱系身份转化为细胞命运的机制，并阐明C.线虫和其他生物。

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.