Abstract
A unique feature of the germ cell lineage is the generation of totipotency. A critical event in this context is DNA demethylation and the erasure of parental imprints in mouse primordial germ cells (PGCs) on embryonic day 11.5 (E11.5) after they enter into the developing gonads1,2. Little is yet known about the mechanism involved, except that it is apparently an active process. We have examined the associated changes in the chromatin to gain further insights into this reprogramming event. Here we show that the chromatin changes occur in two steps. The first changes in nascent PGCs at E8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP-1 (NAP111), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. We therefore suggest that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genome-wide DNA demethylation. On the basis of the timing of the observed events, we propose that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.
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Acknowledgements
The authors thank N. Miller for technical assistance and expertise with FACS sorting and S. Jackson for stimulating discussions and critical reading of the manuscript. Additionally, we thank D. Tremethick, P. Adams and T. Jenuwein for sharing their antibodies. K.A. was a recipient of a Marie Curie and a Newton Trust fellowships, F.C. was a holder of a Marie Curie Fellowship and U.C.L. was supported by a Wellcome Trust PhD studentship. This work was funded by grants from the Wellcome Trust to M.A.S.
Author Contributions P.H. designed and performed the experiments and analysed the data. K.A. performed the analysis of chromatin in early PGCs. T.W., N.L., G.A. and R.S. were involved in the histone variant studies. U.C.L., F.C. and C.L. helped to prepare the samples for cryosectioning and FACS sorting. G.A. and R.S. contributed to experimental design. M.A.S. was involved in the experimental design and, together with P.H., wrote the paper.
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One of the authors, F.C., was temporarily on the staff at Nature while the manuscript was being reviewed, but was not in any way involved in this process.
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Hajkova, P., Ancelin, K., Waldmann, T. et al. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452, 877–881 (2008). https://doi.org/10.1038/nature06714
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DOI: https://doi.org/10.1038/nature06714
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