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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

2012-08-30 | E-GEOD-40335 | biostudies-arrayexpress

Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

Project description:SOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. How temporal fluctuations in their expression levels bias lineage commitment is unknown. Here we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cells towards both neuroectodermal and mesendodermal fates. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.

2019-09-23 | GSE126554 | GEO

Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

Project description:Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

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An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feedback Interactions [methylation]

Project description:Cell fate decisions during development are governed by multi-factorial regulatory mechanisms including chromatin remodelling, DNA methylation, binding of transcription factors to specific loci, RNA transcription and protein synthesis. However, the mechanisms by which such regulatory 'dimensions' coordinate cell fate decisions are currently poorly understood. Here we quantified the multi-dimensional molecular changes that occur in mouse embryonic stem cells (mESCs) upon depletion of Estrogen related receptor beta (Esrrb), a key pluripotency regulator. Analyses of coordinated expression changes identified strikingly different epigenetic regulatory patterns of pluripotency and differentiation states. Comparative analyses of expression changes subsequent to depletion of Esrrb or Nanog, indicated that a system of interlocked feed-forward loops involving both factors plays a central part in regulating the timing of mESC fate decisions. Taken together, our meta-analyses support a hierarchical model in which pluripotency is maintained by an Oct4-Sox2 regulatory module, while the timing of differentiation is regulated by a Nanog-Esrrb

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An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feedback Interactions [gene expression]

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An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feedback Interactions [ChIP-seq]

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NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers [ChIP-seq]

Project description:Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice, where its precise role is yet unclear. We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate. Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.

2016-01-11 | GSE71932 | GEO

Single cell RNA seq of mouse embryonic stem cell line E14 with 2C::tbGFP reporter treated with Retinoic Acid for different time periods

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Chromatin immunoprecipitation of Oct4 and nanog in mouse embryonic stem cells to enable comparison of regulatory networks obtained by ChIP-Chip and ChIP-PET

Project description:Genome-wide approaches have begun to elucidate the transcriptional and epigenetic regulatory networks responsible for pluripotency in embryonic stem (ES) cells. Chromatin Immunoprecipitation (ChIP) followed either by hybridization to a microarray platform (ChIP-chip), or by DNA sequencing (ChIP-PET), has identified the genomic-binding targets of the ES cell transcription factors Oct4 and Nanog in humans and mice, respectively. A central issue that remains to be resolved is the concordance of the data obtained by these methods, given the differences between the two techniques. Here, we report the identification of the Oct4 and Nanog genomic targets in mouse ES cells by ChIP-Chip and have compared the data with binding data identified previously by ChIP-PET. Binding data have also been combined with Oct4 and Nanog RNAi knockdown expression profiling data in ES cells. Surprisingly, we find a substantial difference between the regions that identified exclusively by one of the two techniques. In both studies, however, targets identified by either technique contain a number of genes that are differentially expressed on Oct4 or Nanog knockdown, and have been implicated in cell-fate determination events. This study provides a comparison between the data obtained by different genomic platform, and offers a more comprehensive picture of the stem cell transcriptional network.

2008-11-04 | E-TABM-410 | biostudies-arrayexpress

The Oct4 and Nanog transcription network that regulates pluripotency in mouse embryonic stem cells

Project description:A) We profiled gene expression changes during ES cell differentiation B) We profiled gene expression changes when Pou5f1 or Nanog is knockdown upon RNAi Keywords: Array Based

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