Abstract
Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic stability in ES cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once during nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis-specific homologous recombination genes, which encode proteins that are colocalized with ZSCAN4 on telomeres. Furthermore, Zscan4 knockdown shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by passage eight. Together, our data show a unique mode of genome maintenance in ES cells.
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Acknowledgements
We would like to thank T. Hamatani, Y. Nakatake, M. Monti, L. Xin, B. Binder and A. A. Sharov for discussion; Y. Piao, C. Nguyen, D. Eckley, I. Goldberg, D. Dudekula and I. Stanghellini for technical assistance; P. Soriano for providing ROSA26-floxed LacZ cells; and H. Niwa for providing ROSA-tet-inducible system. This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
Author Contributions M.Z., G.F., L.V.S., A.N., M.T., S.-L.L., C.A.S., H.G.H., H.-T.Y., F.E.I. and R.P.W. designed and performed experiments. M.S.H.K. conceived and supervised the project. M.Z. and M.S.H.K. wrote the manuscript. All authors participated in the discussion.
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Zalzman, M., Falco, G., Sharova, L. et al. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464, 858–863 (2010). https://doi.org/10.1038/nature08882
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DOI: https://doi.org/10.1038/nature08882
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