Interpreting and Deploying Genomic Information During Animal Development

 描述(由申请人提供)：本提案中涉及的问题的共同主题是基因表达是如何由顺式调控模块(CRM)及其在动物发育期间结合的转录因子控制的。在个性化医学的新兴时代，这个问题的答案变得越来越重要，因为我们现在有能力对数千个基因组进行测序，并识别与从癫痫到肥胖等各种疾病相关的DNA序列的变化。然而，当DNA序列的变化映射到基因组的非蛋白质编码部分时，我们几乎无法解释这些变化。该项目将通过建立评估Hox转录因子家族在体内如何发挥作用的方法，帮助弥合我们知识中的这一差距。在接下来的几年里，一个目标是将已知的关于Hox转录因子的特异性扩展到更活体的水平，特别是打破允许这些转录因子在体内选择生物相关结合位点的序列密码。第二个主要目标是更深层次地了解多个转录因子和CRM如何相互协调，以在正确的细胞和正确的发育时间调节基因。对于这最后一套 在实验中，重点放在果蝇腿的近轴-远轴是如何在发育过程中建立的。

 DESCRIPTION (provided by applicant): The common theme underlying the questions being addressed in this proposal is how gene expression is controlled by cis-regulatory modules (CRMs) and the transcription factors that they bind during animal development. Answers to this question are becoming increasingly important in the emerging era of Personalized Medicine, since we now have the ability to sequence thousands of genomes and to identify changes in DNA sequences that correlate with diseases ranging from epilepsy to obesity. However, when changes in DNA sequence map to the non-protein coding portion of the genome, we are nearly helpless in interpreting these changes. This project will help bridge this gap in our knowledge by establishing methods to assess how the Hox family of transcription factors function in vivo. In the next several years, one goal is to extend what has been learned about Hox transcription factor specificity to a more in vivo level, in particular, to break the sequence code that allows these TFs to select biologically relevant binding sites in vivo. A second major goal is to understand at a deeper level how multiple transcription factors and CRMs coordinate with each other to regulate genes in the right cells and at the correct developmental time. For this last set of experiments, the focus is on how the proximo-distal axis of the Drosophila leg is established during development.