Abstract
The expression of the transcription factors Oct4, Sox2, and Nanog is commonly associated with pluripotency of mouse embryonic stem (ES) cells. However, recent observations suggest that ES cell populations are heterogeneous with respect to the expression of Nanog and that individual ES cells reversibly change their Nanog expression level. Furthermore, it has been shown that cells exhibiting a low Nanog level are more likely to undergo differentiation. Applying a novel mathematical transcription factor network model we explore mechanisms and feedback regulations to describe the observed variation of the Nanog levels in mouse ES cells. In particular we show that these variations can occur under different assumptions yielding similar experimental characteristics. Based on model predictions we propose experimental strategies to distinguish between these explanations. Concluding from our results we argue that the heterogeneity with respect to the Nanog concentrations is most likely a functional element to control the differentiation propensity of an ES cell population. Furthermore, we provide a conceptual framework that consistently explains Nanog variability and a potential “gate-keeper” function of Nanog expression with respect to the control of ES cell differentiation.
Highlights
Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst
Over the last years it has been demonstrated that especially the transcription factors Oct4 and Sox2 play a crucial role in this maintenance process by directing the gene expression in ES cells through a cooperative interaction [5]
Previous network models of the central pluripotency genes regularly assumed a direct positive feedback regulation from Nanog acting on Oct4 and Sox2
Summary
Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst. Under appropriate culture conditions these cells can be maintained and expanded in an undifferentiated state over many passages, a feature commonly referred to as self-renewal. The maintenance of the pluripotent state of ES cells over many self-renewing divisions is associated with a characteristic (and stabilized) expression pattern of particular genes. Over the last years it has been demonstrated that especially the transcription factors Oct and Sox play a crucial role in this maintenance process by directing the gene expression in ES cells through a cooperative interaction [5]. Knockout experiments of either Oct or Sox disabled the self-renewal ability of ES cells [6,7]. This duo of transcription factors (TF) is supported by a third factor, Nanog, which seems to be almost important for self-renewal. It has been shown that targeted overexpression of Nanog obviates the requirement for extrinsic signals to block differentiation, preventing ES cells from differentiation under conditions in which they would otherwise differentiate [10]
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