Abstract
BackgroundTo facilitate deciphering underlying transcriptional regulatory circuits in mouse embryonic stem (ES) cells, recent ChIP-seq data provided genome-wide binding locations of several key transcription factors (TFs); meanwhile, existing efforts profiled gene expression in ES cells and in their early differentiated state. It has been shown that the gene expression profiles are correlated with the binding of these TFs. However, it remains unclear whether other TFs, referred to as cofactors, participate the gene regulation by collaborating with the ChIP-seq TFs.ResultsBased on our analyses of the ES gene expression profiles and binding sites of potential cofactors in vicinity of the ChIP-seq TF binding locations, we identified a list of co-binding features that show significantly different characteristics between different gene expression patterns (activated or repressed gene expression in ES cells) at a false discovery rate of 10%. Gene classification with a subset of the identified features achieved up to 20% improvement over classification only based on the ChIP-seq TFs. More than 1/3 of reasoned regulatory roles of cofactor candidates involved in these features are supported by existing literatures. Finally, the predicted target genes of the majority candidates present expected expression change in another independent data set, which serves as a supplementary validation of these candidates.ConclusionsOur results revealed a list of combinatorial genomic features that are significantly associated with gene expression in ES cells, suggesting potential cofactors of the ChIP-seq TFs for gene regulation.
Highlights
To facilitate deciphering underlying transcriptional regulatory circuits in mouse embryonic stem (ES) cells, recent ChIP-seq data provided genome-wide binding locations of several key transcription factors (TFs); existing efforts profiled gene expression in ES cells and in their early differentiated state
Hypothesis of existence of cofactors We first define gene sets of our interest and introduce some existing findings about the main factors based on the ChIP-seq data, and present their interplay results to motivate our hypothesis of existence of cofactors and further analyses
Two gene sets have been identified: The genes whose expression is higher at ES stage than at DF stage with a fold change > 2 and P-value< 0.05 in a two-sample comparison, and the genes that have significantly lower expression at ES stage comparing with expression at DF stage under the same cutoffs
Summary
To facilitate deciphering underlying transcriptional regulatory circuits in mouse embryonic stem (ES) cells, recent ChIP-seq data provided genome-wide binding locations of several key transcription factors (TFs); existing efforts profiled gene expression in ES cells and in their early differentiated state. Together with Oct, Sox explains the first three lineages present in preimplantation development; both factors are essential to epiblast formation, and in their absence trophectoderm is formed [3]. Nanog, another master factor, can bypass leukemia inhibitory factor (LIF)/STAT3 to maintain ES cell self-renewal [4,5], and Nanog-deficient ES cells lose pluripotency and differentiate into extraembryonic endoderm lineage [5]
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