Transcription factor networks in embryonic stem cells and testicular cancer and the definition of epigenetics.

The stem cell phenotype of human and murine ES cells has recently been shown to be maintained by a self-stabilizing network of transcription factors, NANOG, OCT4, and SOX2. These factors maintain their own and each other's transcription, activating, by combinatorial interactions, genes responsible for the ES cell phenotype while repressing genes required for differentiation. This 'core circuitry' interacts with an 'expanded circuitry' encompassing signal transduction and chromatin regulator proteins. During ES cell differentiation the crucial transcription factors are down-regulated by epigenetic mechanisms, including DNA methylation. Aberrant activation of the ES transcription factor network elicited by increased dosage of an embryonic gene cluster at 12p including NANOG, together with additional genetic and epigenetic alterations, appears to be a crucial event in the genesis of testicular germ cell cancers. Intriguingly, the ES cell transcription factor network fits current as well as past definitions of 'epigenetic'.