During the past year, our research has made substantial progress. In our efforts to better understand the function of the Myc proto-oncogene in human ES cells, we have identified a key novel cofactor for Myc in stem cells called Miz-1. Myc and Miz-1 have coordinate genomic functions such that while each factor can regulate gene expression independently, they frequently work in tandem together. When Myc and Miz-1 cooperate, their function together is most often to repress expression of differentiation-associated genes, particularly Hox genes. These data support a new model in which Myc maintains pluripotency in human ES cells and induces pluripotency in iPS cells by working with Miz-1 to keep differentiation genes turned off. Myc levels normally decrease during differentiation, which we theorize initiates a trigger allowing differentiation to proceed normally. High levels of Myc as are observed in cancer may permanently keep differentiation genes off contributing to the formation of the cancer. We have also found in our studies that Myc and Miz-1 genomic binding is associated with specific epigenetic states. When acting separately, Myc and Miz-1 bind to and maintain epigenetically active regions of the genome, but interestingly when they bind the genome together, they maintain a repressed epigenetic state. In other studies we have identified a novel factor that can substitute for Myc in iPS cell formation and we have made substantial progress in characterizing its function. In addition, we have identified novel protein cofactors of Myc that are specific to ESC that shed significant new light into how Myc functions to maintain pluripotency.