Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
BMC Genomics. 2012 Jul 3;13:301. doi: 10.1186/1471-2164-13-301.
Combinatorial histone modification is an important epigenetic mechanism for regulating chromatin state and gene expression. Given the rapid accumulation of genome-wide histone modification maps, there is a pressing need for computational methods capable of joint analysis of multiple maps to reveal combinatorial modification patterns.
We present the Semi-Supervised Coherent and Shifted Bicluster Identification algorithm (SS-CoSBI). It uses prior knowledge of combinatorial histone modifications to guide the biclustering process. Specifically, co-occurrence frequencies of histone modifications characterized by mass spectrometry are used as probabilistic priors to adjust the similarity measure in the biclustering process. Using a high-quality set of transcriptional enhancers and associated histone marks, we demonstrate that SS-CoSBI outperforms its predecessor by finding histone modification and genomic locus biclusters with higher enrichment of enhancers. We apply SS-CoSBI to identify multiple cell-type-specific combinatorial histone modification states associated with human enhancers. We show enhancer histone modification states are correlated with the expression of nearby genes. Further, we find that enhancers with the histone mark H3K4me1 have higher levels of DNA methylation and decreased expression of nearby genes, suggesting a functional interplay between H3K4me1 and DNA methylation that can modulate enhancer activities.
The analysis presented here provides a systematic characterization of combinatorial histone codes of enhancers across three human cell types using a novel semi-supervised biclustering algorithm. As epigenomic maps accumulate, SS-CoSBI will become increasingly useful for understanding combinatorial chromatin modifications by taking advantage of existing knowledge.
SS-CoSBI is implemented in C. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/SS-CoSBI.gz.
组合组蛋白修饰是调节染色质状态和基因表达的重要表观遗传机制。鉴于全基因组组蛋白修饰图谱的快速积累，迫切需要能够联合分析多个图谱以揭示组合修饰模式的计算方法。
我们提出了半监督一致和移位双聚类识别算法（SS-CoSBI）。它使用组合组蛋白修饰的先验知识来指导双聚类过程。具体来说，使用质谱法表征的组蛋白修饰的共现频率作为概率先验来调整双聚类过程中的相似性度量。使用一组高质量的转录增强子和相关的组蛋白标记，我们证明 SS-CoSBI 通过找到具有更高增强子富集的组蛋白修饰和基因组位置双聚类来优于其前身。我们应用 SS-CoSBI 来识别与人类增强子相关的多种细胞类型特异性组合组蛋白修饰状态。我们表明增强子组蛋白修饰状态与附近基因的表达相关。此外，我们发现具有 H3K4me1 组蛋白标记的增强子具有更高水平的 DNA 甲基化和附近基因表达降低，这表明 H3K4me1 和 DNA 甲基化之间存在功能相互作用，可以调节增强子活性。
这里呈现的分析使用一种新的半监督双聚类算法，对三种人类细胞类型中的增强子的组合组蛋白代码进行了系统表征。随着表观基因组图谱的积累，SS-CoSBI 将通过利用现有知识，越来越有助于理解组合染色质修饰。
SS-CoSBI 是用 C 语言实现的。源代码可在 http://www.healthcare.uiowa.edu/labs/tan/SS-CoSBI.gz 免费获得。
