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

BMC Genomics

Research Article

Chih-yu Chen¹  Jennifer A Mitchell¹  Quaid Morris² 

[1] Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, M5S 3G5, Toronto, ON, Canada;Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada;

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

DOI  :  10.1186/1471-2164-13-152

 received in 2011-09-30, accepted in 2012-04-26,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundEpigenetic 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.ResultsCross 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.ConclusionsThe 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.

【 授权许可】

Unknown   
© Chen et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.