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BMC Genomics  2011 

Searching ChIP-seq genomic islands for combinatorial regulatory codes in mouse embryonic stem cells

DOI: 10.1186/1471-2164-12-515

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Abstract:

Based 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.Our 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.A set of core transcription factors (TFs) have been reported to regulate the self-renewal and pluripotency of mouse embryonic stem (ES) cells. Oct4 has long been regarded as one of the master regulators in ES cells. Oct4-deficient embryos fail to produce pluripotent inner cell mass [1]. Furthermore, while repression of Oct4 allows trophectoderm development, a less-than-twofold increase in Oct4 expression drives differentiation into primitive endoderm and mesoderm [2]. Together with Oct4, Sox2 explains the first three lineages present in preimplantation development; both factors are essential to epiblast formation, and in their absence trophec-toderm 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].In addition to the three master TFs, implications of the r

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