期刊
GENES & DEVELOPMENT
卷 25, 期 3, 页码 238-250出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.607311
关键词
pluripotency factors; Nanog; definitive endoderm; Eomes; Activin/Nodal signaling; human embryonic stem cells
资金
- A*STAR Graduate Academy (Singapore)
- DFG
- MRC center
- MRC
- Cambridge Hospitals National Institute for Health Research Biomedical Research Center
- Medical Research Council [G0800784B, G0701448, G0800784] Funding Source: researchfish
- MRC [G0800784, G0701448] Funding Source: UKRI
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.
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