During the current funding period we have made substantial progress toward achieving the goals of the three specific aims of the proposal. Toward the first aim, Test the hypothesis that Myc regulates hESC self-renewal and pluripotency, we have achieved several milestones. We have created hESC with Myc loss-of-function and determined a key role for endogenous Myc in regulating hESC self-renewal and pluripotency. We have also made substantial progress in addressing the objectives of the second aim, Study Myc regulation of hESC and iPS cell epigenetics. We have successfully completed the first phase of functional genomics studies (ChIP-chip) for endogenous c-Myc and N-Myc in hESC, finding a surprising dual role for Myc proteins in regulating the epigenetic state of hESC. In specific aim three, Discovery of novel enhancers and suppressors of human iPS formation, we have achieved two key goals already. First, we have created the novel cDNA library needed for screens and second we have begun conducting screens for pluripotency modulators. We have also found key new putative pluripotency factors in a novel proteomics screen. Together these studies have resulted in several key publications and demonstrate substantial progress after only two years of funding.