Developing Informatics Technologies to Model Cancer Gene Regulation

项目摘要 反式作用因子如何调节癌症中全基因组基因的表达还知之甚少，这激发了一种新的研究。 越来越多的ChIP-seq、DNase-seq和ATAC-seq（简称为“顺式序列”）实验， 全基因组转录因子结合位点和染色质状态。重要的生物学见解 通过对顺反子数据的计算分析获得，特别是当与其他已发表的 顺式组和基因表达数据集。然而，大多数癌症生物学家发现计算数据分析和 顺式组和表观基因组数据的整合是其癌症基因中最具限制性的瓶颈 由于缺乏信息学专业知识和计算基础设施， 大量的公开数据。我们以前开发了顺反子分析管道（AP） 和Cistrome数据浏览器（DB）来克服这一挑战。这项建议的目的是扩大 Cistrome AP和DB的功能，以改善收集，管理，分析，集成， 可视化和分发顺反子和相关数据类型。灵活直观的用户 经验将使实验癌症生物学家能够创建更有洞察力的转录模型， 癌症研究中的表观遗传基因调控。 具体来说，我们建议改进和扩展我们现有的Cistrome分析管道（http：//cistrome.org/ap） 和Cistrome数据浏览器（http：//cistrome.org/db）的基础设施和接口， 这些技术解决了顺反子数据分析的四个关键方面。首先，我们将设计、开发和 通过用户友好的界面部署软件，以改进自动化数据收集、处理和 注释。这将使未发布的和公共的顺反子数据能够被联合分析并转换为 可用于综合分析的格式和统计表达式。第二，我们将制定方法 使用所有可用的顺式组数据来估算未公开表示的TF结合/细胞类型组合 储存库。第三，我们将开发系统，使基因表达数据与顺反子数据相结合 阐明调控机制。第四，我们将开发基于网络的交互式工具， 数百个顺反子样本在多个分辨率。最后，我们将开展外联活动， 改进了Cistrome的功能、用户界面、与其他工具的互操作性，促进了Cistrome数据的使用 在癌症研究中。

PROJECT SUMMARY How trans-acting factors regulate genome-wide gene expression in cancer is poorly understood, motivating an increasing number of ChIP-seq, DNase-seq, and ATAC-seq (simplified as “cistrome”) experiments to map genome-wide transcription factor binding sites and chromatin status. Significant biological insights have been gained through the computational analysis of cistrome data, especially when integrated with other published cistrome and gene expression data sets. However, most cancer biologists find computational data analysis and integration of cistrome and epigenome data to be the single most limiting bottleneck in their cancer gene regulation studies due to the lack of informatics expertise and computational infrastructure relative to the extraordinary volume of publicly available data. We have previously developed Cistrome Analysis Pipeline (AP) and Cistrome Data Browser (DB) to overcome this challenge. The objective of this proposal is to expand the functionality of Cistrome AP and DB to improve the collection, management, analysis, integration, visualization, and dissemination of cistrome and related data types. A flexible and intuitive user experience will empower experimental cancer biologists to create more insightful models of transcriptional and epigenetic gene regulation in cancer research. Specifically, we propose to improve and extend our existing Cistrome Analysis Pipeline (http://cistrome.org/ap) and Cistrome Data Browser (http://cistrome.org/db) infrastructure and interface by developing informatics technologies that address four critical aspects of cistrome data analysis. First, we will design, develop, and deploy software through a user-friendly interface to improve automated data collection, processing, and annotation. This will enable unpublished and public cistrome data to be jointly analyzed and converted into formats and statistical expressions that can be used for integrative analysis. Second, we will develop methods to use all available cistrome data to impute TF binding/cell-type combinations that are not represented in public repositories. Third, we will develop systems to allow gene expression data to be integrated with cistrome data to elucidate regulatory mechanisms. Fourth, we will develop interactive web based tools for the visualization of hundreds of cistrome samples at multiple resolutions. Finally, we will engage in outreach activities to improve improve Cistrome functions, user interface, interoperability with other tools, and promote the Cistrome data use in cancer research.