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Open Access Highly Accessed Research article

Enhancer identification in mouse embryonic stem cells using integrative modeling of chromatin and genomic features

Chih-yu Chen1, Quaid Morris2 and Jennifer A Mitchell1*

Author Affiliations

1 Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON, , M5S 3G5, Canada

2 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada

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BMC Genomics 2012, 13:152  doi:10.1186/1471-2164-13-152

Published: 26 April 2012

Abstract

Background

Epigenetic modifications, transcription factor (TF) availability and differences in chromatin folding influence how the genome is interpreted by the transcriptional machinery responsible for gene expression. Enhancers buried in non-coding regions are found to be associated with significant differences in histone marks between different cell types. In contrast, gene promoters show more uniform modifications across cell types. Here we used histone modification and chromatin-associated protein ChIP-Seq data sets in mouse embryonic stem (ES) cells as well as genomic features to identify functional enhancer regions. Using co-bound sites of OCT4, SOX2 and NANOG (co-OSN, validated enhancers) and co-bound sites of MYC and MYCN (limited enhancer activity) as enhancer positive and negative training sets, we performed multinomial logistic regression with LASSO regularization to identify key features.

Results

Cross validations reveal that a combination of p300, H3K4me1, MED12 and NIPBL features to be top signatures of co-OSN regions. Using a model from 10 signatures, 83% of top 1277 putative 1 kb enhancer regions (probability greater than or equal to 0.8) overlapped with at least one TF peak from 7 mouse ES cell ChIP-Seq data sets. These putative enhancers are associated with increased gene expression of neighbouring genes and significantly enriched in multiple TF bound loci in agreement with combinatorial models of TF binding. Furthermore, we identified several motifs of known TFs significantly enriched in putative enhancer regions compared to random promoter regions and background. Comparison with an active H3K27ac mark in various cell types confirmed cell type-specificity of these enhancers.

Conclusions

The top enhancer signatures we identified (p300, H3K4me1, MED12 and NIPBL) will allow for the identification of cell type-specific enhancer regions in diverse cell types.

Keywords:
Enhancer; Embryonic stem cells; Transcription factor; ChIP-Seq; Histone methylation; Regulation of gene expression