Unknown,Transcriptomics,Genomics,Proteomics

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Retinoic acid induces Snai1 in stem cells of the preimplantation blastocyst to initiate differentiation

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 (EMT) is already expressed in the inner cell mass of the preimplantation blastocysts. In ESCs Snai1 does not respond to TGFÎ± or BMP4 signalling but it is induced by retinoic acid (RA) treatment, which induces the binding, on the Snai1 promoter, of the retinoid receptors RARÎ³ and RXRÎ± the dissociation of the Polycomb repressor compex 2 (PRC2) 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. microarray analysis of embryonic stem cells (ESC) expressing Snail-ER at various time points of induction with 4-OHT

ORGANISM(S): Mus musculus

SUBMITTER: Francesco Neri

PROVIDER: E-GEOD-57854 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Snai1 promotes ESC exit from the pluripotency by direct repression of self-renewal genes.

Galvagni Federico F Lentucci Claudia C Neri Francesco F Dettori Daniela D De Clemente Caterina C Orlandini Maurizio M Anselmi Francesca F Rapelli Stefania S Grillo Michela M Borghi Sara S Oliviero Salvatore S

Stem cells (Dayton, Ohio) 20150301 3

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 treatm ...[more]

PMID: 25504116

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Project description:The self-renewal and differentiation capacities of human pluripotent stem cells (hPSCs) make them good sources of cells for cell transplantation therapy, drug development, and studies of cellular differentiation and development. However, the large numbers of cells necessary for many of these applications require extensive expansion of hPSC cultures, a process that has been associated with applications require extensive expansion of hPSC cultures, a process that has been associated with genetic and epigenetic alterations. We have performed a systematic study over more than 100continuous passages to identify characteristics of culture conditions (including passage method, substrate, and media type) that influence the genetic and epigenetic stability and the phenotypic characteristics of hPSCs. The predominant effects we observed were increased genetic instability with enzymatic passage, higher cell proliferation with feeder-free substrate, and variations among cultures in global gene expression and DNA methylation with time in culture. We observed recurrent duplications in two genomic regions that have been noted in earlier studies to be hotspots for duplication in hPSCs, as well as a previously unreported recurrent deletion of the tumor suppressor gene TP53 in all but one of the long-term culture conditions; the exception was the condition using mechanical passaging on feeder layers. The deletion of TP53 is associated with decreased mRNA expression of TP53, as well as alterations in the expression of several other genes in the TP53 pathway, which taken together indicate a decrease in the function of the TP53 pathway. Our results highlight the need for careful assessment of effects of culture conditions on cells intended for clinical therapies. Total RNA extracted at different passages from Human Embryonic Stem Cells in different culture conditions. Total DNA extracted at different passages from Human Embryonic Stem Cells in different culture conditions.

Dataset Information

Retinoic acid induces Snai1 in stem cells of the preimplantation blastocyst to initiate differentiation

Publications

Snai1 promotes ESC exit from the pluripotency by direct repression of self-renewal genes.

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