How a more plastic chromatin state is maintained and reversed during development is unknown. Heterochromatin-mediated silencing of repetitive elements occurs in differentiated cells. Here, we used repetitive elements, including retrotransposons, as model loci to address how and when heterochromatin forms during development. RNA sequencing throughout early mouse embryogenesis revealed that repetitive-element expression is dynamic and stage specific, with most repetitive elements becoming repressed before implantation. We show that LINE-1 and IAP retrotransposons become reactivated from both parental genomes after fertilization. Chromatin immunoprecipitation for H3K4me3 and H3K9me3 in 2- and 8-cell embryos indicates that their developmental silencing follows loss of activating marks rather than acquisition of conventional heterochromatic marks. Furthermore, short LINE-1 RNAs regulate LINE-1 transcription in vivo. Our data indicate that reprogramming after mammalian fertilization comprises a robust transcriptional activation of retrotransposons and that repetitive elements are initially regulated through RNA.
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We thank L. Tora for support during the initial part of this work, S. Bour for graphic work, Y. Miyanari for advice on RNA FISH, E. Heard (Curie Institute, Paris, France) for the full-length LINE-1 probe, M. Dewannieux and T. Heidmann (Gustave Roussy Institute, Villejuif, France) for the IAP probe, D. Stollar, T. Ye and members of the Torres-Padilla lab for helpful discussions and A.J. Bannister and A. Burton for critical reading of the manuscript. M.-E.T.-P. acknowledges funding from AVENIR/INSERM, ANR-09-Blanc-0114, Epigenesys NoE and ERC-2011-StG 280840 “NuclearPotency.” Work in P.C.'s laboratory is supported by a Research Grant for RIKEN Omics Science Center from MEXT and a Funding Program for the Next Generation World Leading Researchers. A.F. was supported by a post-doctoral fellowship from the Fondation pour la Recherche Medicale.
The authors declare no competing financial interests.
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Fadloun, A., Le Gras, S., Jost, B. et al. Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA. Nat Struct Mol Biol 20, 332–338 (2013). https://doi.org/10.1038/nsmb.2495
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