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Zscan4 regulates telomere elongation and genomic stability in ES cells

Nature volume 464, pages 858–863 (2010)Cite this article

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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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Figure 1: Zscan4 is transiently expressed in ES cells.
Figure 2: Characterization of Zscan4 -knockdown cells.
Figure 3: Zscan4 regulates telomere length.
Figure 4: Zscan4 promotes T-SCE but inhibits spontaneous SCE in non-telomeric regions.
Figure 5: ZSCAN4 forms foci on telomeres along with meiosis-specific homologous recombination mediators.

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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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  1. Geppino Falco & Sung-Lim Lee

    Present address: Present addresses: Istituto di Ricerche Genetiche Gaetano Salvatore Biogem s.c.ar.l., Ariano Irpino 83031, Italy (G.F.); College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongnam 660701, Republic of Korea (S.-L.L.).,

Authors and Affiliations

  1. Developmental Genomics and Aging Section, Laboratory of Genetics,,

    Michal Zalzman, Geppino Falco, Lioudmila V. Sharova, Akira Nishiyama, Marshall Thomas, Sung-Lim Lee, Carole A. Stagg, Hien G. Hoang, Hsih-Te Yang & Minoru S. H. Ko

  2. Research Resources Branch, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA ,

    Fred E. Indig & Robert P. Wersto

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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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