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Telomere lengthening early in development

Abstract

Stem cells and cancer cells maintain telomere length mostly through telomerase1,2,3. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts3. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.

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Figure 1: Telomere lengthening in one- to two-cell embryos.
Figure 2: Telomerase-independent telomere elongation in one-to two-cell embryos.
Figure 3: T-SCE in early cleavage embryos revealed by CO-FISH.
Figure 4: Expression and localization of Rad50 in early cleavage embryos.

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Acknowledgements

We thank V. Zakian and J. Petrini for advice on the Rad50 and telomere recombination work, P. Lansdorp for providing TFL telomere-analysis software and advice on Q-FISH analysis, and I. Hickson for providing anti-BLM antibodies. This work was partly supported by the Women and Infants Hospital/Brown Faculty Research (D.L.K. and L.L.), National Nature Science Foundation China (L.L.), James and Esther King Biomedical Research Program (L.L.) and the MCyT, European Union and the Josef Steiner Award 2003 (M.A.B.).

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L.L. and D.L.K. designed the study. L.L., S.M.B., M.O., P.M., C.L., L.Z., C.W., E.C., L.S. and A.S. performed the experiments. M.A.B. provided the TRKO mice and advice. L.L. and D.L.K. wrote the paper, and S.M.B, M.A.B. and A.S. revised the manuscript.

Corresponding authors

Correspondence to Lin Liu or David L. Keefe.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3, S4, S5 and S6 (PDF 2315 kb)

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Liu, L., Bailey, S., Okuka, M. et al. Telomere lengthening early in development. Nat Cell Biol 9, 1436–1441 (2007). https://doi.org/10.1038/ncb1664

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