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Activin/Nodal signaling is necessary to maintain pluripotency of human embryonic stem cells (hESCs) and to induce their differentiation toward endoderm. However, the mechanisms by which Activin/Nodal signaling achieves these opposite functions remain unclear. To unravel these mechanisms, we examined the transcriptional network controlled in hESCs by Smad2 and Smad3, which represent the direct effectors of Activin/Nodal signaling. These analyses reveal that Smad2/3 participate in the control of the core transcriptional network characterizing pluripotency, which includes Oct-4, Nanog, FoxD3, Dppa4, Tert, Myc, and UTF1. In addition, similar experiments performed on endoderm cells confirm that a broad part of the transcriptional network directing differentiation is downstream of Smad2/3. Therefore, Activin/Nodal signaling appears to control divergent transcriptional networks in hESCs and in endoderm. Importantly, we observed an overlap between the transcriptional network downstream of Nanog and Smad2/3 in hESCs; whereas, functional studies showed that both factors cooperate to control the expression of pluripotency genes. Therefore, the effect of Activin/Nodal signaling on pluripotency and differentiation could be dictated by tissue specific Smad2/3 partners such as Nanog, explaining the mechanisms by which signaling pathways can orchestrate divergent cell fate decisions.

Original publication

DOI

10.1002/stem.666

Type

Journal article

Journal

Stem cells

Publication Date

08/2011

Volume

29

Pages

1176 - 1185

Keywords

Activins, Base Sequence, Cell Differentiation, Cell Line, Chromatin Immunoprecipitation, Embryonic Stem Cells, Endoderm, Gene Regulatory Networks, Genes, Reporter, Homeodomain Proteins, Humans, Luciferases, Firefly, Nanog Homeobox Protein, Nodal Protein, Promoter Regions, Genetic, Sequence Analysis, DNA, Smad2 Protein, Smad3 Protein, Stem Cells