Dissecting the Regulation of Gene Expression during C. elegans Embryogenesis

描述(申请人提供)：我建议开发工具、数据集和方法，用于在全基因组范围内鉴定秀丽线虫胚胎发育过程中受转录因子调控的基因。在职业发展阶段，我将使用我们在沃特斯顿实验室开发的方法，在线虫胚胎中生成具有细胞分辨率的转录因子活性的初始图谱。同时，我将开发技术，以促进有效地识别胚胎中转录因子的下游靶标。一旦进入我自己的实验室，我将扩展这些方法，在基因组规模上识别和表征许多转录因子的功能靶标，并探索转录因子如何结合来调节基因表达。职业发展阶段将是这项工作的关键，因为需要开发方法，也因为我提议制作的转录因子表达图将提供一个关键的整合平台，供在选择用于全基因组分析的因子时使用，并在解释结果数据时使用。 与公众健康相关：了解转录因子在发育过程中如何发挥作用的知识可能会提供有关相同的转录因子在癌症中不适当激活时如何发挥作用的信息。此外，这项研究中确定的受发育重要转录因子调控的基因的人类同源基因可能在正常发育和疾病中发挥作用。

DESCRIPTION (provided by applicant): I propose to develop tools, datasets and methods for the genome-wide identification of genes regulated by transcription factors during the embryonic development of Caenorhabditis elegans. During the career development phase, I will use methods we have developed in the Waterston lab to generate an initial map of transcription factor activity with cellular resolution in the C. elegans embryo. In parallel I will develop technology to facilitate the efficient identification of downstream targets of transcription factors in the embryo. Once in my own lab, I will extend these methods to identify and characterize functional targets of many transcription factors on a genomic scale and to explore how transcription factors combine to regulate gene expression. The career development phase will be critical for this effort because of the need for development of methods, and because the transcription factor expression map I propose to produce will provide a critical integrating platform to use when choosing factors for genome-wide analysis and when interpreting the resulting data. Relevance to public health: Knowledge of how transcription factors act in development may provide information about how the same transcription factors function in cancers when inappropriately activated. Furthermore, human orthologs of genes identified in this study as regulated by developmentally important transcription factors may play roles in both normal development and disease.