title: Snai1 promotes ESC exit from the pluripotency by direct repression of self-renewal genes.
abstract: Although much is known about the pluripotency self-renewal circuitry, the molecular events that lead embryonic stem cells (ESCs) exit from pluripotency and begin differentiation are largely unknown. We found that the zinc finger transcription factor Snai1, involved in gastrulation and epithelial-mesenchymal transition, is already expressed in the inner cell mass of the preimplantation blastocysts. In ESCs, Snai1 does not respond to TGFβ or BMP4 signaling but it is induced by retinoic acid treatment, which induces the binding, on the Snai1 promoter, of the retinoid receptors RARγ and RXRα, the dissociation of the Polycomb repressor complex 2 which results in the decrease of H3K27me3, and the increase of histone H3K4me3. Snai1 mediates the repression of pluripotency genes by binding directly to the promoters of Nanog, Nr5a2, Tcl1, c-Kit, and Tcfcp2l1. The transient activation of Snai1 in embryoid bodies induces the expression of the markers of all three germ layers. These results suggest that Snai1 is a key factor that triggers ESCs exit from the pluripotency state and initiate their differentiation processes.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Galvagni
authors.forename: Claudia
authors.initials: C
authors.lastname: Lentucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.forename: Daniela
authors.initials: D
authors.lastname: Dettori
authors.forename: Caterina
authors.initials: C
authors.lastname: De Clemente
authors.forename: Maurizio
authors.initials: M
authors.lastname: Orlandini
authors.forename: Francesca
authors.initials: F
authors.lastname: Anselmi
authors.forename: Stefania
authors.initials: S
authors.lastname: Rapelli
authors.forename: Michela
authors.initials: M
authors.lastname: Grillo
authors.forename: Sara
authors.initials: S
authors.lastname: Borghi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014212:Tretinoin
keywords: Differentiation; Embryonic stem cells; Nanog; Retinoic acid; Self-renewal; Snai1; Snail