Abstract
BackgroundCombinatorial 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.ResultsWe 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.ConclusionsThe 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.Availability and implementationSS-CoSBI is implemented in C. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/SS-CoSBI.gz.
Highlights
Combinatorial histone modification is an important epigenetic mechanism for regulating chromatin state and gene expression
The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/SS-COherent and Shifted Bicluster Identification algorithm (CoSBI).gz
Using a set of known transcriptional enhancers and histone modifications characterized by both mass spectrometry (MS) and ChIPSeq protocol, we demonstrate that SS-CoSBI outperforms its predecessor by finding biclusters with higher enrichment of enhancers
Summary
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. The histone code hypothesis postulates that multiple histone modifications act in a combinatorial fashion to specify distinct chromatin states, which in turn regulate gene activities [1,2]. The MS-based approach is not yet amenable to high-throughput analysis though progress has been made constantly. Given their higher resolution and more quantitative nature, combinatorial histone modifications obtained from MS-based studies provide valuable complementary information to genome-wide combinatorial histone modification analysis based on ChIP technologies
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