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A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.

Chickarmane V, Peterson C - PLoS ONE (2008)

Bottom Line: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency.With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment.Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology, California Institute of Technology, Pasadena, California, United States of America.

ABSTRACT

Background: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.

Methodology/principal findings: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.

Conclusions: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.

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The essential TF interactions between Gata-6 and Nanog, which determine the endoderm lineage.In this condensed motif, the factor O/S represents both Oct4-Sox2 as well as Oct4. Both Nanog and Gata-6 are positively induced by Oct4. The dashed red line indicates a hypothesis, which emerges as a necessity from a model analysis (see Main Text).
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pone-0003478-g002: The essential TF interactions between Gata-6 and Nanog, which determine the endoderm lineage.In this condensed motif, the factor O/S represents both Oct4-Sox2 as well as Oct4. Both Nanog and Gata-6 are positively induced by Oct4. The dashed red line indicates a hypothesis, which emerges as a necessity from a model analysis (see Main Text).

Mentions: Extracting from Figure 1, the interactions between Oct4, Nanog and Gata-6, we deduce the simple motif displayed in Figure 2, which shows O/S, a proxy for Oct4 or Oct4-Sox2, that activates both Nanog and Gata-6 (the latter is assumed, since over-expression of Oct4 leads to induction of Gata-6 [14]). Also shown is the mutual antagonism between Gata-6 and Nanog, as well as the Gata-6 and Nanog positive self-interactions. From Figure 2, we argue that for low O/S, when Nanog is not fully turned on, the default state is that Gata-6 is on. This is to be expected since, Gata-6 is auto-regulating [9], and hence can maintain stable levels. Thereafter, increasing O/S, should lead to activation of Nanog, such that the latter increases its levels, and at some threshold of O/S, switches Gata-6 off. If we now demand, that GATA-6 exhibits biphasic response with respect to O/S, then as O/S continues to increase, since Gata-6 must be somehow switched on, Nanog must be switched off. It seems inconsistent however, that O/S, which induces Nanog, can switch Gata-6 on, where the latter itself is suppressed by Nanog. One mechanism, however, that could give rise to this, is if we assume that Nanog is suppressed by the heterodimer, O/S–Gata-6. This leads to the following consequence: At the higher threshold of O/S, when Gata-6 levels begin to increase, the heterodimer O/S–Gata-6 suppresses Nanog, thereby, allowing Gata-6 to ultimately switch on. Translating these assumptions into mathematical terms, we describe the evolution of Nanog and Gata-6 concentration levels as the ordinary differential equations (Eq. 1) given in Materials and Methods. In Figure 3, the steady state curves (which are obtained by setting the right hand side of Eq. 1 to zero) for Nanog and Gata-6 reflect the biphasic behavior with respect to the concentration of O/S. The steady state plot also shows a hysteretic behavior, which arises essentially due to the cooperative effect of autoregulation of Gata-6, and suppression of Nanog. Hence, this simple model can help explain the regulation required between the mutually antagonistic pair like Nanog/Gata-6, such that Nanog displays a “bell shaped” curve, whereas, Gata-6 displays the “inverted bell shaped” curve.


A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.

Chickarmane V, Peterson C - PLoS ONE (2008)

The essential TF interactions between Gata-6 and Nanog, which determine the endoderm lineage.In this condensed motif, the factor O/S represents both Oct4-Sox2 as well as Oct4. Both Nanog and Gata-6 are positively induced by Oct4. The dashed red line indicates a hypothesis, which emerges as a necessity from a model analysis (see Main Text).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2566811&req=5

pone-0003478-g002: The essential TF interactions between Gata-6 and Nanog, which determine the endoderm lineage.In this condensed motif, the factor O/S represents both Oct4-Sox2 as well as Oct4. Both Nanog and Gata-6 are positively induced by Oct4. The dashed red line indicates a hypothesis, which emerges as a necessity from a model analysis (see Main Text).
Mentions: Extracting from Figure 1, the interactions between Oct4, Nanog and Gata-6, we deduce the simple motif displayed in Figure 2, which shows O/S, a proxy for Oct4 or Oct4-Sox2, that activates both Nanog and Gata-6 (the latter is assumed, since over-expression of Oct4 leads to induction of Gata-6 [14]). Also shown is the mutual antagonism between Gata-6 and Nanog, as well as the Gata-6 and Nanog positive self-interactions. From Figure 2, we argue that for low O/S, when Nanog is not fully turned on, the default state is that Gata-6 is on. This is to be expected since, Gata-6 is auto-regulating [9], and hence can maintain stable levels. Thereafter, increasing O/S, should lead to activation of Nanog, such that the latter increases its levels, and at some threshold of O/S, switches Gata-6 off. If we now demand, that GATA-6 exhibits biphasic response with respect to O/S, then as O/S continues to increase, since Gata-6 must be somehow switched on, Nanog must be switched off. It seems inconsistent however, that O/S, which induces Nanog, can switch Gata-6 on, where the latter itself is suppressed by Nanog. One mechanism, however, that could give rise to this, is if we assume that Nanog is suppressed by the heterodimer, O/S–Gata-6. This leads to the following consequence: At the higher threshold of O/S, when Gata-6 levels begin to increase, the heterodimer O/S–Gata-6 suppresses Nanog, thereby, allowing Gata-6 to ultimately switch on. Translating these assumptions into mathematical terms, we describe the evolution of Nanog and Gata-6 concentration levels as the ordinary differential equations (Eq. 1) given in Materials and Methods. In Figure 3, the steady state curves (which are obtained by setting the right hand side of Eq. 1 to zero) for Nanog and Gata-6 reflect the biphasic behavior with respect to the concentration of O/S. The steady state plot also shows a hysteretic behavior, which arises essentially due to the cooperative effect of autoregulation of Gata-6, and suppression of Nanog. Hence, this simple model can help explain the regulation required between the mutually antagonistic pair like Nanog/Gata-6, such that Nanog displays a “bell shaped” curve, whereas, Gata-6 displays the “inverted bell shaped” curve.

Bottom Line: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency.With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment.Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology, California Institute of Technology, Pasadena, California, United States of America.

ABSTRACT

Background: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.

Methodology/principal findings: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.

Conclusions: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.

Show MeSH
Related in: MedlinePlus