A predictive modeling approach for cell line-specific long-range regulatory interactions.
A predictive modeling approach for cell line-specific long-range regulatory interactions.
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DOI：
10.1093/nar/gkv865
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发表时间：
2015-10-15
影响因子：
14.9
通讯作者：
Sridharan R
中科院分区：
文献类型：
--
作者：
Roy S;Siahpirani AF;Chasman D;Knaack S;Ay F;Stewart R;Wilson M;Sridharan R
远端增强子和靶基因之间的长程调控相互作用对于组织特异性基因表达是重要的。以细胞系特异性方式在基因组规模上鉴定这些相互作用，特别是使用尽可能少的数据集，是一个重大挑战。我们开发了一种新的计算方法，启动子和远程增强子的调控相互作用预测（涟漪），该方法将已发表的染色体构象捕获（3C）数据集与一组最小的调控基因组数据集相结合，以细胞系特异性的方式预测增强子-启动子相互作用。我们的研究结果表明，CTCF，RAD 21，一个通用的转录因子（TBP）和染色质激活标记是重要的决定因素的增强子-启动子相互作用。为了预测新细胞系中的相互作用并生成全基因组相互作用图谱，我们开发了涟漪的集成版本，并将其应用于五种人类细胞系中的相互作用。使用现有的ChIA-PET和Hi-C数据集对这些预测进行的计算验证表明，涟漪准确地预测了增强子和启动子之间的相互作用。增强子-启动子相互作用倾向于组织成代表协调调节的基因组的子网络，所述基因组富集特定的生物过程和顺式调节元件。总的来说，我们的工作提供了一个系统的方法来预测和解释增强子-启动子相互作用的全基因组细胞类型的特定方式，使用一些实验上易于处理的测量。
Long range regulatory interactions among distal enhancers and target genes are important for tissue-specific gene expression. Genome-scale identification of these interactions in a cell line-specific manner, especially using the fewest possible datasets, is a significant challenge. We develop a novel computational approach, Regulatory Interaction Prediction for Promoters and Long-range Enhancers (RIPPLE), that integrates published Chromosome Conformation Capture (3C) data sets with a minimal set of regulatory genomic data sets to predict enhancer-promoter interactions in a cell line-specific manner. Our results suggest that CTCF, RAD21, a general transcription factor (TBP) and activating chromatin marks are important determinants of enhancer-promoter interactions. To predict interactions in a new cell line and to generate genome-wide interaction maps, we develop an ensemble version of RIPPLE and apply it to generate interactions in five human cell lines. Computational validation of these predictions using existing ChIA-PET and Hi-C data sets showed that RIPPLE accurately predicts interactions among enhancers and promoters. Enhancer-promoter interactions tend to be organized into subnetworks representing coordinately regulated sets of genes that are enriched for specific biological processes and cis-regulatory elements. Overall, our work provides a systematic approach to predict and interpret enhancer-promoter interactions in a genome-wide cell-type specific manner using a few experimentally tractable measurements.