New Publication: “Quantifying ES cells: A ß-catenin driven protein interaction network that buffers Oct4 to maintain pluripotency”

Muñoz-Descalzo, S., Rue, P., Faunes, F., Hayward, P., Jakt, L.M., Balayo, C., Garcia Ojalvo, J. and Martinez Arias, A. (2013) A competitive protein interaction network buffers Oct4-mediated differentiation to promote pluripotency in embryonic stem cells. Mol. Sys. Biol. 9 Article number: 694  doi:10.1038/msb.2013.49

The model that represents the competition between the different complexes and a comparison of the distributions of Oct4, Nanog and ß-catenin in ES cells grown in Serum and LIF or in 2i conditions; in the top is data, at the bottom is the result of the simulations of the model on the left.

Pluripotency refers to the property of a cell population to give rise to all cell types of an organism. Embryonic Stem (ES) cells are pluripotent and are able to self renew this property in culture. ES cells have become an important focus of research. From the biomedical point of view because they hold a promise for regenerative medicine, from the basic science point of view because they offer a useful experimental system to understand how cells make decisions in development.

Work over the last ten years has identified a core set of transcription factors that are necessary and sufficient for the establishment and the maintenance of pluripotency with two of these factors, Oct4 and Nanog, at the center of the network. However, how they function together to achieve this state has remained elusive. Most of the models focus on transcriptional gene regulatory networks assembled from interactions between these factors. However we have shown recently that pluripotency is characterized not by the absolute amount of any of these factors but by specific ratios of Nanog and Oct4 (Muñoz Descalzo et al. 2012 Correlations between the levels of Nanog and Oct4 as a signature for naïve pluripotency in mouse embryonic stem cells Stem Cells 30, 2683-2691). Furthermore, it appears that the amount of ß-catenin is key to the stability of the state. In this work we use a combination of quantitative immunofluorescence, genetics and modelling to show that pluripotency is dependent on a competitive protein network whose function is to buffer the levels of Oct4. ß-catenin emerges as the anchor of the network and the one element whose fluctuations determine the stability of the state.

While not doing away with Gene Regulatory Networks, this study raises the power of protein networks as the information processing units of the cell.