A Cis Regulatory map of the Drosophila Genome

描述(申请人提供)：果蝇是研究人类顺式调节的理想模式生物。它的基因组共享人类基因组的结构和主要特征；所有主要的转录因子家族，既有基本的机制，也有位置特定的因子；发育基因的总体调控结构，如HOX簇；许多控制器官或组织特性的“主调控”转录因子蛋白，如PAX6/Eyes和Distalless。在许多情况下，人的蛋白质在果蝇中的功能与果蝇的蛋白质一样。除了共享的生物学之外，苍蝇还提供了哺乳动物物种尚未提供的强大的实验工具。它的小基因组只有130Mb，可以在人类还无法达到的分辨率下进行全基因组的系统实验。此外，共有12个完全测序的物种提供了最丰富的比较基因组数据集之一，其强大的功能足以识别整个基因组中调节因子的单个功能结合位点。最后，丰富的高通量实验技术使我们能够在体内验证功能预测。在这个建议中，我们利用这些独特的功能，使用实验和计算相结合的方法，生成果蝇基因组的全面顺式调控图。我们将根据顺式调控基序和语法、染色质状态和转录因子结合来识别苍蝇启动子区域、短程和长程增强子、绝缘子和阻遏子区域及其定义特征。 该项目作为全面绘制人类基因组中功能调控元件图谱的试点。开发的方法和策略将是告知人类基因组的关键。此外，所获得的知识对于理解由于基因调控失灵引起的许多人类疾病和障碍将是无价的。果蝇是这个项目的理想模式系统，因为它的基因组大小、实验资源和比较基因组学能力，同时保留了人类基因组的所有主要特征，用于基因调控研究。

DESCRIPTION (provided by the applicant): Drosophila presents an ideal model organism for the study of human cis-regulation. Its genome shares the structure and major features of the human genome; all major families of transcription factors, both the basal machinery and site-specific factors; the overall regulatory structure of developmental genes such as the Hox clusters; many of the "master regulatory" transcription factor proteins such as PAX6/eyeless and Distalless that control organ or tissue identity. In many cases, human proteins function in Drosophila just as well as Drosophila proteins. In addition to the shared biology, the fly also offers powerful experimental tools not yet available for mammalian species. Its small genome size, at 130 Mb, is amenable to genome-wide systematic experimentation at a resolution not yet achievable in the human. Additionally, a total of 12 fully sequenced species provide one of the richest comparative genomic datasets, powerful enough to identify individual functional binding sites of regulators across the entire genome. Finally, the wealth of high throughput experimental techniques enables us to validate functional predictions in vivo. In this proposal, we exploit these unique features to produce a comprehensive cis-regulatory map of the Drosophila genome, using a combined experimental and computational approach. We will identify fly promoter regions, short and long range enhancers, insulator and repressor regions, and their defining characteristics based on cis-regulatory motifs and grammars, chromatin state, and transcription factor binding. This project serves as a pilot for the full-scale mapping of functional regulatory elements in the human genome. The methods and strategies developed will be crucial for informing the human genome. In addition, the body of knowledge gained will be invaluable in the understanding of many human diseases and disorders due to regulatory malfunction of gene regulation. Drosophila is an ideal model system for this project, for its compact genome size, experimental resources, and comparative genomics power, while retaining all the major characteristics of the human genome for the study of gene regulation.