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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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Recruitment of REST to Repressed GenesSignificantly changing genes (p < 0.01) were ranked by their fold expression change in response to DN:REST (green, increased by DN:REST; red, decreased). For a sliding window, the fraction of genes within 100 kb of a REST PET cluster is plotted. The dashed line represents the mean value for all genes in the genome.
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pbio-0060256-g006: Recruitment of REST to Repressed GenesSignificantly changing genes (p < 0.01) were ranked by their fold expression change in response to DN:REST (green, increased by DN:REST; red, decreased). For a sliding window, the fraction of genes within 100 kb of a REST PET cluster is plotted. The dashed line represents the mean value for all genes in the genome.

Mentions: It was somewhat surprising that the vast majority of the genes with an associated REST binding site were not derepressed by DN:REST. We noted that the most up-regulated genes have sites in very close proximity to their TSS, often within 1 kb (Figure 5C and 5D). To investigate this further, we plotted the fold change in expression for each gene versus the distance of that gene to the nearest mapped RE1 site (Figure S13). This analysis clearly indicated a strong bias for the most differentially expressed genes to have an RE1 site proximal to its TSS. It is noteworthy that this bias for RE1 sites was associated only with the genes up-regulated, but not those down-regulated, by DN:REST, which is consistent with the expectation that REST acts as a repressor (Figure 6).


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)

Recruitment of REST to Repressed GenesSignificantly changing genes (p < 0.01) were ranked by their fold expression change in response to DN:REST (green, increased by DN:REST; red, decreased). For a sliding window, the fraction of genes within 100 kb of a REST PET cluster is plotted. The dashed line represents the mean value for all genes in the genome.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060256-g006: Recruitment of REST to Repressed GenesSignificantly changing genes (p < 0.01) were ranked by their fold expression change in response to DN:REST (green, increased by DN:REST; red, decreased). For a sliding window, the fraction of genes within 100 kb of a REST PET cluster is plotted. The dashed line represents the mean value for all genes in the genome.
Mentions: It was somewhat surprising that the vast majority of the genes with an associated REST binding site were not derepressed by DN:REST. We noted that the most up-regulated genes have sites in very close proximity to their TSS, often within 1 kb (Figure 5C and 5D). To investigate this further, we plotted the fold change in expression for each gene versus the distance of that gene to the nearest mapped RE1 site (Figure S13). This analysis clearly indicated a strong bias for the most differentially expressed genes to have an RE1 site proximal to its TSS. It is noteworthy that this bias for RE1 sites was associated only with the genes up-regulated, but not those down-regulated, by DN:REST, which is consistent with the expectation that REST acts as a repressor (Figure 6).

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