Concise review: The Sox2-Oct4 connection: critical players in a much larger interdependent network integrated at multiple levels.

The transcription factors Sox2 and Oct4 have been a major focus of stem cell biology since the discovery, more than 10 years ago, that they play critical roles during embryogenesis. Early work established that these two transcription factors work together to regulate genes required for the self-renewal and pluripotency of embryonic stem cells (ESC). Surprisingly, small changes (∼twofold) in the levels of either Oct4 or Sox2 induce the differentiation of ESC. Consequently, ESC must maintain the levels of these two transcription factors within narrow limits. Genome-wide binding studies and unbiased proteomic screens have been conducted to decipher the complex roles played by Oct4 and Sox2 in the transcriptional circuitry of ESC. Together, these and other studies provide a comprehensive understanding of the molecular machinery that sustains the self-renewal of ESC and restrains their differentiation. Importantly, these studies paint a landscape in which Oct4 and Sox2 are part of a much larger interdependent network composed of many transcription factors that are interconnected at multiple levels of function.