title: Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors.
abstract: 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.
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brown
authors.forename: Adrian
authors.initials: A
authors.lastname: Teo
authors.forename: Siim
authors.initials: S
authors.lastname: Pauklin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hannan
authors.forename: Candy H-H
authors.initials: CH
authors.lastname: Cho
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.forename: Leah
authors.initials: L
authors.lastname: Vardy
authors.forename: N Ray
authors.initials: NR
authors.lastname: Dunn
authors.forename: Matthew
authors.initials: M
authors.lastname: Trotter
authors.forename: Roger
authors.initials: R
authors.lastname: Pedersen
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
mesh_terms: D028341:Activins / Q000378:metabolism*; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000378:metabolism; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; C526007:NODAL protein, human; D000071317:Nanog Homeobox Protein; D055457:Nodal Protein; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D028341:Activins; D049409:Luciferases, Firefly