SVM-based Analysis of the Fine Scale Structure of Regulatory Elements

描述（由申请人提供）：ENCODE项目产生了大量高质量的功能基因组数据集，这些数据集有可能极大地影响我们对细胞特异性调控元件功能的特定机制和一般原理的理解。我们建议建立一个基于支持向量机的计算模型来预测这些数据集的增强子并解析它们的精细尺度结构。我们将利用一种综合的方法来研究这些精细尺度的特征，结合新的计算发展、ENCODE数据集的统计分析、人类序列变异的系统评分和高通量验证，以提高我们对DNA序列特征和变异如何促进调控功能的理解。基于我们之前使用k-mer特征从基因组DNA序列中预测哺乳动物增强子的工作，我们提出了对序列特征处理的改进，以促进对长k-mer特征的统计稳健估计并提高空间分辨率。这种方法不依赖于以前的生物学知识，并揭示了一系列新的tf和辅助因子，这些因子指定了它们的细胞特异性活性。我们将在ENCODE dna -seq和ChIP-seq数据上训练该模型，并在可用的人类细胞系和小鼠数据集中编目调控元件。此外，该模型对个体特征对增强子活性的贡献做出了具体预测，因此我们建议通过直接量化荧光素酶报告系统中这些元素突变的影响来实验测试这组预测。最后，我们将在一组目标细胞系中评估和实验评估特定人类snp的预测影响。该项目将对调控元件功能的预测模型和序列变异如何影响疾病的理解做出重大贡献。

DESCRIPTION (provided by applicant): The ENCODE projects have generated large high-quality functional genomic datasets which have the potential to dramatically impact our understanding of the specific mechanisms and general principles of the function of cell-specific regulatory elements. We propose to develop an SVM-based computational model to predict enhancers from these datsets and resolve their fine- scale structure. We will utilize an integrative approach to investigate these fine scale features which combines novel computational development, statistical analysis of ENCODE datasets, systematic scoring of human sequence variation, and high throughput validation to improve our understanding of how DNA sequence features and variation contribute to regulatory function. Based on our previous work using k-mer features to predict mammalian enhancers from genomic DNA sequence, we propose improvements in the treatment of sequence features which facilitate statistically robust estimation of long k-mer features and improved spatial resolution. This approach does not rely on previous biological knowledge, and uncovers the sets of novel TFs and cofactors which specify their cell-specific activity. We will train this model on ENCODE DNase-seq and ChIP-seq data and catalogue the regulatory elements in the available human cell-line and mouse datasets. In addition, this model makes specific predictions of the contributions of individual features to enhancer activity, so we propose to experimentally test this set of predictions by directly quantifying the impact of mutation of these elements in a luciferase reporter system. Finally we will evaluate and experimentally assess the predicted impact of specific human SNPs in a set of targeted cell lines. This project should contribute significantly toward a predictive model of regulatory element function and an understanding of how sequence variation impacts disease.