Systems Biology

Systemic View of Stem Cells

Science Signaling  24 Nov 2009:
Vol. 2, Issue 98, pp. ec377
DOI: 10.1126/scisignal.298ec377

Control of cell fate is an example of a complex biological regulatory system in which changes in just one or a few components can propagate through a regulatory network to cause profound and permanent changes in the fundamental properties of a cell and how it functions. Lu et al. addressed the challenging task of characterizing, at a broad or “systems” scale, the events that underlie the differentiation of mouse embryonic stem cells (ESCs). They treated ESCs with short hairpin RNA designed to deplete cells of mRNA encoding Nanog, a transcription factor that has an important role in maintaining ESCs in a pluripotent state, thus initiating differentiation. They then used large-scale assays to measure the response of cells over the next several days: Changes in chromatin structure were monitored by chromatin immunoprecipitation and microarray analysis of histone acetylation. Localization of RNA polymerase II after chromatin immunoprecipitation was used to monitor transcription. Microarrays were used to monitor mRNA abundance. And, finally, mass spectrometry was used to measure changes in abundance of proteins in the nucleus. By comparing the responses of genes, mRNAs, and proteins over time, the authors could interpret whether primary regulation of a protein occurred by a transcriptional or posttranscriptional mechanism. Some intriguing properties could be noted: Changes in the abundance of many nuclear proteins were not accompanied by changes in mRNA abundance, emphasizing the role of translational and posttranslational regulation in cell fate decisions. Of genes that showed changes in transcriptional activity, only about half showed corresponding changes in protein abundance. Among the latter were several genes encoding essential ESC factors that function to retain pluripotency. Analysis of the timing of various changes also revealed insights into the direction of information flow in the network. The authors note that their manipulation of the cells (depletion of Nanog) is not a normal physiological event but argue that it nevertheless provides a system in which the dynamic complexity of cell fate decisions can be understood in terms of alterations in multiple layers of regulatory events.

R. Lu, F. Markowetz, R. D. Unwin, J. T. Leek, E. M. Airoldi, B. D. MacArthur, A. Lachmann, R. Rozov, A. Ma’ayan, L. A. Boyer, O. G. Troyanskaya, A. D. Whetton, I. R. Lemischka, Systems-level dynamic analyses of fate change in murine embryonic stem cells. Nature 462, 358–362 (2009). [PubMed]