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REST regulates distinct transcriptional networks in embryonic and neural stem cells.

Johnson R, Teh CH, Kunarso G, Wong KY, Srinivasan G, Cooper ML, Volta M, Chan SS, Lipovich L, Pollard SM, Karuturi RK, Wei CL, Buckley NJ, Stanton LW - PLoS Biol. (2008)

Bottom Line: We investigated how these distinct biological roles are effected at a genomic level.In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog.We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore.

ABSTRACT
The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays important but distinct regulatory roles in embryonic (ESC) and neural (NSC) stem cells. We investigated how these distinct biological roles are effected at a genomic level. We present integrated, comparative genome- and transcriptome-wide analyses of transcriptional networks governed by REST in mouse ESC and NSC. The REST recruitment profile has dual components: a developmentally independent core that is common to ESC, NSC, and differentiated cells; and a large, ESC-specific set of target genes. In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog. We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.

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A Model of REST Regulation of Pluripotency and Differentiation in ESCYellow and orange panels contain a selection of genes that are commonly targeted by REST, Nanog, Oct4 and Sox2. Red panel contains Wnt pathway-related genes (as identified by the Panther database) that are bound by REST. Activating (arrows) and repressive (bars) regulation is inferred from ChIP binding data.
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pbio-0060256-g008: A Model of REST Regulation of Pluripotency and Differentiation in ESCYellow and orange panels contain a selection of genes that are commonly targeted by REST, Nanog, Oct4 and Sox2. Red panel contains Wnt pathway-related genes (as identified by the Panther database) that are bound by REST. Activating (arrows) and repressive (bars) regulation is inferred from ChIP binding data.

Mentions: Together, our results suggest a model in which the intersection of activating (Oct4, Sox2, Nanog) and repressive (REST) transcriptional signals control ESC pluripotency (Figure 8). The outcome of these opposing forces is expression levels of a large number of genes that are appropriate for the pluripotent state. In addition to potentially antagonizing pluripotency by binding genes such as Nanog and Zfp206, REST also appears to promote pluripotency through repression of multiple components of the Wnt pathway. The regulatory relationships suggested by our whole-genome mapping study will need to be functionally confirmed in future by knock-down of REST, which will lead to derepression of target gene expression; furthermore, it is possible that such regulation takes place only during stages of differentiation subsequent to that represented by the ESC as discussed above. Regardless of such details, however, our findings show that REST has a complex role in both promoting and antagonizing the pluripotent state.


REST regulates distinct transcriptional networks in embryonic and neural stem cells.

Johnson R, Teh CH, Kunarso G, Wong KY, Srinivasan G, Cooper ML, Volta M, Chan SS, Lipovich L, Pollard SM, Karuturi RK, Wei CL, Buckley NJ, Stanton LW - PLoS Biol. (2008)

A Model of REST Regulation of Pluripotency and Differentiation in ESCYellow and orange panels contain a selection of genes that are commonly targeted by REST, Nanog, Oct4 and Sox2. Red panel contains Wnt pathway-related genes (as identified by the Panther database) that are bound by REST. Activating (arrows) and repressive (bars) regulation is inferred from ChIP binding data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2573930&req=5

pbio-0060256-g008: A Model of REST Regulation of Pluripotency and Differentiation in ESCYellow and orange panels contain a selection of genes that are commonly targeted by REST, Nanog, Oct4 and Sox2. Red panel contains Wnt pathway-related genes (as identified by the Panther database) that are bound by REST. Activating (arrows) and repressive (bars) regulation is inferred from ChIP binding data.
Mentions: Together, our results suggest a model in which the intersection of activating (Oct4, Sox2, Nanog) and repressive (REST) transcriptional signals control ESC pluripotency (Figure 8). The outcome of these opposing forces is expression levels of a large number of genes that are appropriate for the pluripotent state. In addition to potentially antagonizing pluripotency by binding genes such as Nanog and Zfp206, REST also appears to promote pluripotency through repression of multiple components of the Wnt pathway. The regulatory relationships suggested by our whole-genome mapping study will need to be functionally confirmed in future by knock-down of REST, which will lead to derepression of target gene expression; furthermore, it is possible that such regulation takes place only during stages of differentiation subsequent to that represented by the ESC as discussed above. Regardless of such details, however, our findings show that REST has a complex role in both promoting and antagonizing the pluripotent state.

Bottom Line: We investigated how these distinct biological roles are effected at a genomic level.In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog.We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore.

ABSTRACT
The maintenance of pluripotency and specification of cellular lineages during embryonic development are controlled by transcriptional regulatory networks, which coordinate specific sets of genes through both activation and repression. The transcriptional repressor RE1-silencing transcription factor (REST) plays important but distinct regulatory roles in embryonic (ESC) and neural (NSC) stem cells. We investigated how these distinct biological roles are effected at a genomic level. We present integrated, comparative genome- and transcriptome-wide analyses of transcriptional networks governed by REST in mouse ESC and NSC. The REST recruitment profile has dual components: a developmentally independent core that is common to ESC, NSC, and differentiated cells; and a large, ESC-specific set of target genes. In ESC, the REST regulatory network is highly integrated into that of pluripotency factors Oct4-Sox2-Nanog. We propose that an extensive, pluripotency-specific recruitment profile lends REST a key role in the maintenance of the ESC phenotype.

Show MeSH