Zscan4 Is Activated after Telomere Shortening in Mouse Embryonic Stem Cells

Summary

ZSCAN4 is a DNA-binding protein that functions for telomere elongation and genomic stability. In vivo, it is specifically expressed at the two-cell stage during mouse development. In vitro, it is transiently expressed in mouse embryonic stem cells (ESCs), only in 5% of the population at one time. Here we attempted to elucidate when, under what circumstances, Zscan4 is activated in ESCs. Using live cell imaging, we monitored the activity of Zscan4 together with the pluripotency marker Rex1. The lengths of the cell cycles in ESCs were diverse. Longer cell cycles were accompanied by shorter telomeres and higher activation of Zscan4. Since activation of Zscan4 is involved in telomere elongation, we speculate that the extended cell cycles accompanied by Zscan4 activation reflect the time for telomere recovery. Rex1 and Zscan4 did not show any correlation. Taken together, we propose that Zscan4 is activated to recover shortened telomeres during extended cell cycles, irrespective of the pluripotent status.

Graphical Abstract

Highlights

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  At longer cell cycles, telomeres are shorter

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  Zscan4 is activated when the cell cycles become long

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  After the activation of Zscan4, the next cell cycle becomes short

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  We propose Zscan4 is activated for telomere maintenance irrespective of pluripotency

Abstract

Zscan4 is a rejuvenation factor that is transiently expressed in ESCs. By retrospective analyses of live imaging data, Nakai-Futatsugi and Niwa show that Zscan4 is activated when cell cycles become long, presumably sensing shortened telomeres irrespective of the pluripotent status. The results suggest that Zscan4 is activated for genomic maintenance, which is not necessarily related to the two-cell-stage-like status of ESCs.