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Understanding the molecular mechanisms controlling early cell fate decisions in mammals is a major objective toward the development of robust methods for the differentiation of human pluripotent stem cells into clinically relevant cell types. Here, we used human embryonic stem cells and mouse epiblast stem cells to study specification of definitive endoderm in vitro. Using a combination of whole-genome expression and chromatin immunoprecipitation (ChIP) deep sequencing (ChIP-seq) analyses, we established an hierarchy of transcription factors regulating endoderm specification. Importantly, the pluripotency factors NANOG, OCT4, and SOX2 have an essential function in this network by actively directing differentiation. Indeed, these transcription factors control the expression of EOMESODERMIN (EOMES), which marks the onset of endoderm specification. In turn, EOMES interacts with SMAD2/3 to initiate the transcriptional network governing endoderm formation. Together, these results provide for the first time a comprehensive molecular model connecting the transition from pluripotency to endoderm specification during mammalian development.

Original publication

DOI

10.1101/gad.607311

Type

Journal article

Journal

Genes Dev

Publication Date

01/02/2011

Volume

25

Pages

238 - 250

Keywords

Activins, Animals, Biomarkers, Cell Differentiation, Cell Line, Endoderm, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Homeodomain Proteins, Humans, Mice, Nanog Homeobox Protein, Nodal Protein, Octamer Transcription Factor-3, Pluripotent Stem Cells, SOXB1 Transcription Factors, T-Box Domain Proteins