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 similarity 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 the ES cells experience Zscan4-positive state by 9 passages. By knocking down Zscan4 activation by an shRNA, we have found that Zscan4 is essential for long-term maintenance of genomic integrity and to mediate a regulated telomere recombination in normal undifferentiated ES cells, therefore making it indispensable for 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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Zalzman, Michal; Falco, Geppino; Sharova, Lioudmila V et al. (2010) Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464:858-63
Nishiyama, Akira; Xin, Li; Sharov, Alexei A et al. (2009) Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell 5:420-33
Stanghellini, Ilaria; Falco, Geppino; Lee, Sung-Lim et al. (2009) Trim43a, Trim43b, and Trim43c: Novel mouse genes expressed specifically in mouse preimplantation embryos. Gene Expr Patterns 9:595-602