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Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity

ABSTRACT: A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach, that includes high-throughput single cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced more a homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops play a role in controlling both ES cell fate decisions and population variability.

ORGANISM(S): Mus musculus

PROVIDER: GSE40335 | GEO | 2012/08/30

SECONDARY ACCESSION(S): PRJNA173635

REPOSITORIES: GEO

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Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity

Project description:A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach, that includes high-throughput single cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced more a homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops play a role in controlling both ES cell fate decisions and population variability. Total of 30 samples, 10 conditions in triplicates; Cell samples were harvested at day0 (Dox present, Nanog expressing, NgR day0 +Dox), and at days 1,3 and 5 days after dox withdrawal (NgR day1 -Dox, NgR day3 -Dox and NgR day5 -Dox respectively). Additionally, at each time-point a set of samples was further treated with a twelve-hour pulse of dox before being harvested (NgR day1+ 12h Dox, NgR day3+12h Dox and NgR day5+12h Dox) and compared with untreated control samples harvested at the same time (NgR day1- 12h Dox, NgR day3-12h Dox and NgR day5-12h Dox) . All time points were performed in triplicates. We performed Affymetrix GeneChip® Mouse Gene 1.0 ST arrays analyses of mouse embryonic stem cell gene expression profiles at each time point. BD MacArthur and A Sevilla contributed equally to this study

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