A Cis Regulatory map of the Drosophila Genome

描述（由申请人提供）：果蝇是研究人类顺式调控的理想模式生物。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，包括基础机制和位点特异性因子；发育基因（如Hox基因簇）的整体调控结构；许多“主调控”转录因子蛋白，如PAX6/ eyeeless和Distalless，控制器官或组织的身份。在许多情况下，人类蛋白质在果蝇体内的功能和果蝇蛋白质一样好。除了共享生物学之外，苍蝇还提供了哺乳动物物种尚未拥有的强大实验工具。它的基因组很小，只有130兆字节，适合进行全基因组系统实验，其分辨率尚无法在人类身上实现。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，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。在本提案中，我们利用这些独特的特征，利用实验和计算相结合的方法，制作了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确定果蝇启动子区域、短程和远程增强子、绝缘子和抑制子区域，以及它们的定义特征。

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.