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Title:
REST maintains self-renewal and pluripotency of embryonic stem cells | Nature
Description:
The neuronal repressor protein REST (also known as NRSF) maintains self renewal and pluripotency in embryonic stem cells through suppression of the miRNA-21, and is therefore a newly identified member of the transcriptional network maintaining stem cells in a pluripotent state. Knocking down its activity by using of siRNA or deletion of one allele caused loss of self renewal and led the cells to express differentiated markers. The neuronal repressor REST (RE1-silencing transcription factor; also called NRSF) is expressed at high levels in mouse embryonic stem (ES) cells1, but its role in these cells is unclear. Here we show that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR-21. We found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse ES cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest (Rest+/-) and its short-interfering-RNA-mediated knockdown in mouse ES cells cause a loss of self-renewal—even when these cells are grown under self-renewal conditions—and lead to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintains self-renewal in mouse EB cells. Furthermore, Rest+/- mouse ES cells cultured under self-renewal conditions express substantially reduced levels of several self-renewal regulators, including Oct4 (also called Pou5f1), Nanog, Sox2 and c-Myc, and exogenously added REST in mouse EB cells maintains the self-renewal phenotypes and expression of these self-renewal regulators. We also show that in mouse ES cells, REST is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added REST express lower levels of these miRNAs, EB cells, Rest+/- ES cells and ES cells treated with short interfering RNA targeting Rest express higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR-21, specifically suppresses the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2 and c-Myc. Thus, REST is a newly discovered element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells.
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Topics {✒️}
crispr/cas9-based genome-wide screening nature portfolio permissions reprints short-interfering-rna-mediated knockdown privacy policy germ-line-competent embryonic stem advertising nature cell biol social media re1-silencing transcription factor nature rev nature med stanton nature fisher nature early embryonic development nature genet /neuron-restrictive silencer factor nature 444 nature 453 nature neural stem/progenitor cells jørgensenzhou-feng chenamanda brain tumor center neuronal repressor rest/nrsf personal data springerlink instant access data protection permissions mouse embryonic stem rest/nrsf target genes author contributions author correspondence newly discovered element embryonic stem cells exogenously added rest neuronal repressor rest neural stem cells privacy α-fetoprotein transcription interconnected regulatory network promoter analysis based stem cell differentiation mouse es cells differentiating mouse es gene regulatory network blocking neuronal differentiation mouse eb cells jan parker-thornburg mirna target sites protein interaction network
Questions {❓}
- Can controversies be put to REST?
- Is REST a regulator of pluripotency?
- Is REST required for ESC pluripotency?
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description:The neuronal repressor protein REST (also known as NRSF) maintains self renewal and pluripotency in embryonic stem cells through suppression of the miRNA-21, and is therefore a newly identified member of the transcriptional network maintaining stem cells in a pluripotent state. Knocking down its activity by using of siRNA or deletion of one allele caused loss of self renewal and led the cells to express differentiated markers. The neuronal repressor REST (RE1-silencing transcription factor; also called NRSF) is expressed at high levels in mouse embryonic stem (ES) cells1, but its role in these cells is unclear. Here we show that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR-21. We found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse ES cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest (Rest+/-) and its short-interfering-RNA-mediated knockdown in mouse ES cells cause a loss of self-renewalâeven when these cells are grown under self-renewal conditionsâand lead to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintains self-renewal in mouse EB cells. Furthermore, Rest+/- mouse ES cells cultured under self-renewal conditions express substantially reduced levels of several self-renewal regulators, including Oct4 (also called Pou5f1), Nanog, Sox2 and c-Myc, and exogenously added REST in mouse EB cells maintains the self-renewal phenotypes and expression of these self-renewal regulators. We also show that in mouse ES cells, REST is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added REST express lower levels of these miRNAs, EB cells, Rest+/- ES cells and ES cells treated with short interfering RNA targeting Rest express higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR-21, specifically suppresses the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2 and c-Myc. Thus, REST is a newly discovered element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells.
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