We have further characterized Zscan4 in mouse 2-cell embryos and in the subpopulation of mouse ES cells. We found that other 2-cell-specific genes are also highly expressed in Zscan4(+) cells. This indicates that the subpopulation of ES cells marked by Zscan4 expression shows some resemblance to 2-cell embryos, whereas the majority of ES cells show similarities to the Inner Cell Mass (ICM) cells in blastocysts. Zscan4 is thus associated with a unique transient state in undifferentiated ES cells, in which other 2-cell embryo-specific genes are activated. By carrying out cell lineage tracing experiments, we have found that, although Zscan4 is expressed only in 5% of ES cells in culture at a given time, essentially all ES cells experience a Zscan4-positive state by 9 passages. By knocking down Zscan4 activation with an shRNA, we have found that Zscan4 is essential for the long-term maintenance of genomic integrity and for mediating a regulated telomere recombination in normal undifferentiated ES cells, therefore making it indispensable for the proper long-term self-renewal in ES cells. We have also found that Zscan4 is involved in the induction and recruitment of the meiosis-specific homologous recombination machinery to telomeres. We are currently investigating whether the activation of Zscan4 can further increase the genome stability in ES and induced pluripotent (iPS) stem cells. We are also investigating the involvement of Zscan4 in DNA repairs.