Computational Models for Mechanisms of Global Transcription

描述（由申请人提供）：ChIP-chip/seq与转录组分析相结合，极大地帮助我们理解了许多生理和病理过程的分子机制。它也留下了未回答的问题，哺乳动物转录调控的组合和上下文特异性的性质，并创造了计算数据集成和建模的挑战。为了解决这些问题，我们提出：1）通过整合转录因子ChIP-chip/seq、顺式元件表观基因组和转录组数据，构建哺乳动物基因组条件特异性组合和概率转录调控模块的计算框架; 2）应用1）中的模型构建全面的概率核受体调节网络，并通过实验验证预测，并使用结果来改进模型; 3）开发并维护一个开源的、公开可用的集成ChIP-chip/seq数据分析管道Cistrome。随着转录因子ChIP-chip/seq、顺式元件表观基因组和转录组数据集的快速增长，我们的方法将整合可用的数据集，推断重要的缺失数据，并从单个数据集中提取最大的知识。我们由此产生的核受体调控网络和计算工具也将成为社区的良好资源。

DESCRIPTION (provided by applicant): ChIP-chip/seq in combination with transcriptome profiling has greatly helped our understanding of the molecular mechanisms underlying many physiological and pathological processes. It has also left unanswered questions on the combinatorial and context-specific nature of mammalian transcription regulation, and created challenges for computational data integration and modeling. To address these challenges, we propose to: 1) develop the computational framework for constructing condition-specific combinatorial and probabilistic transcription regulatory modules in mammalian genomes by integrating transcription factor ChIP-chip/seq, cis-element epigenome and transcriptome data; 2) apply the model in 1) to construct a comprehensive probabilistic nuclear receptor regulatory network, experimentally validate the predictions, and use the results to refine the model; 3) develop and maintain an open source publicly available integrated ChIP-chip/seq data analysis pipeline Cistrome. With rapid growth of transcription factor ChIP-chip/seq, cis-element epigenome, and transcriptome datasets, our methods will integrate the available datasets, infer the important missing data, and extract maximum knowledge from individual datasets. Our resulting nuclear receptor regulatory network and computational tools will also be a good resource for the community.