Smarca4 and Ctbp2 are important for cell fate decisions in embryonic stem cells

Mammalian embryonic stem cells (ESCs) self-renew and have the ability to generate each of the three germ layers, making them a pluripotential source of numerous primitive progenitors and committed lineages. ESCs have three fates: self-renewal, differentiation, and apoptosis. They are also able to make stoichiometric decisions leading to either asymmetric or symmetric cell division. The mechanisms and genes that make up the regulatory network controlling these cell fate and stoichiometric decisions in mouse and human ESCs is largely incomplete.; Several publications have demonstrated an importance of chromatin factors to the ESC regulatory network. In order to identify additional genes that exert an effect on the ESC fate decisions, the candidate genes Smarca4/Brg1 and Ctbp2 were selected from microarray data for their enriched expression in stem cells, chromatin-related activity, and relative obscurity in the field of stem cell biology. RNA interference (RNAi) was used to knockdown gene expression in mouse ESCs (mESCs) and the potential of the manipulated cells to pursue each of the three aforementioned fates was assessed.; The results are indicative of important roles for each candidate gene in stem cell maintenance and regulation of differentiation. It is shown here that the knockdown of Ctbp2 increases the prevalence of ESCs in culture, delays differentiation induced by LIF withdrawal, and introduces developmental changes in mesodermal induction. It is also shown that the knockdown of Smarca4/Brg-1 impairs the self-renewal ability of ESCs by preventing the PI3K cell cycle pathway from efficiently cross talking with the Writ self-renewal pathway. Two models are presented herein and suggest the importance of both Smarca4/Brg-1 and Ctbp2 to the stem cell regulatory network. These models may also contribute to an understanding of stem cell-based oncogenesis.; Biological advances in embryonic stem cell biology are incomplete if not accompanied by an equal consideration of medical therapies, social policies, and national politics. Therefore, this quantitative study concludes with a longitudinal sketch of the national politics and social trends in the human embryonic stem cell debate and a qualitative study of an unprecedented effort at stem cell policy and agency formation in California.