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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 a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability.

SUBMITTER: MacArthur BD

PROVIDER: S-EPMC3507454 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity.

MacArthur Ben D BD Sevilla Ana A Lenz Michel M Müller Franz-Josef FJ Schuldt Berhard M BM Schuppert Andreas A AA Ridden Sonya J SJ Stumpf Patrick S PS Fidalgo Miguel M Ma'ayan Avi A Wang Jianlong J Lemischka Ihor R IR

Nature cell biology 20121028 11

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 ...[more]

PMID: 23103910

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Project description:Heterogeneity is an often unappreciated characteristic of stem cell populations yet its importance in fate determination is becoming increasingly evident. Although gene expression noise has received greater attention as a source of non-genetic heterogeneity, the effects of stochastic partitioning of cellular material during mitosis on population variability have not been researched to date. We examined self-renewing human embryonic stem cells (hESCs), which typically exhibit a dispersed distribution of the pluripotency marker NANOG. In conjunction with our experiments, a multiscale cell population balance equation (PBE) model was constructed accounting for transcriptional noise and stochastic partitioning at division as sources of population heterogeneity. Cultured hESCs maintained time-invariant profiles of size and NANOG expression and the data were utilized for parameter estimation. Contributions from both sources considered in this study were significant on the NANOG profile, although elimination of the gene expression noise resulted in greater changes in the dispersion of the NANOG distribution. Moreover, blocking of division by treating hESCs with nocodazole or colcemid led to a 39% increase in the average NANOG content and over 68% of the cells had higher NANOG level than the mean NANOG expression of untreated cells. Model predictions, which were in excellent agreement with these findings, revealed that stochastic partitioning accounted for 17% of the total noise in the NANOG profile of self-renewing hESCs. The computational framework developed in this study will aid in gaining a deeper understanding of how pluripotent stem/progenitor cells orchestrate processes such as gene expression and proliferation for maintaining their pluripotency or differentiating along particular lineages. Such models will be essential in designing and optimizing efficient differentiation strategies and bioprocesses for the production of therapeutically suitable stem cell progeny.

Dataset Information

Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity.

Publications

Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity.

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