During the past 10 years, remarkable progress has been made in understanding the transcriptional mechanisms that control the biology of stem cells. Given the importance of stem cells in development, regenerative medicine, and cancer, it is no surprise that the pace of discovery continues to accelerate—paradigm-shifting models proposed only a few years ago are quickly giving way to even more sophisticated models of regulation. This review summarizes some of the major advances made in delineating the roles of two transcription factors, Sox2 and Oct-3/4, in stem cell biology. Additionally, unanswered questions related to their mechanisms of action are discussed. When viewed together, it is evident that Sox2 and Oct-3/4 exhibit the major properties expected of master regulators. They are each essential for mammalian development, they help regulate the transcription of other genes that are essential for development, and they influence their own transcription by both positive and negative feedback loops. Moreover, small changes in the levels of either Sox2 or Oct-3/4 trigger the differentiation of embryonic stem (ES) cells. Thus, each functions as a molecular rheostat to control the self-renewal and pluripotency of ES cells. Overall, understanding how Sox2 and Oct-3/4 function mechanistically will not only provide important insights into stem cells in general, but should also have a significant impact on our understanding of induced pluripotent stem (iPS) cells and, hence, the emerging field of regenerative medicine. Copyright © 2009 John Wiley & Sons, Inc.
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