Xist-dependent imprinted X inactivation and the early developmental consequences of its failure
Nature Structural and Molecular Biology
Nature Publishing Group
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Borensztein, M., Syx, L., Ancelin, K., Diabangouaya, P., Picard, C., Liu, T., Liang, J., et al. (2017). Xist-dependent imprinted X inactivation and the early developmental consequences of its failure. Nature Structural and Molecular Biology, 24 (3), 226-233. https://doi.org/10.1038/nsmb.3365
The long noncoding RNA Xist is expressed from only the paternal X chromosome in mouse preimplantation female embryos and mediates transcriptional silencing of that chromosome. In females, absence of Xist leads to postimplantation lethality. Here, through single-cell RNA sequencing of early preimplantation mouse embryos, we found that the initiation of imprinted X-chromosome inactivation absolutely requires Xist. Lack of paternal Xist leads to genome-wide transcriptional misregulation in the early blastocyst and to failure to activate the extraembryonic pathway that is essential for postimplantation development. We also demonstrate that the expression dynamics of X-linked genes depends on the strain and parent of origin as well as on the location along the X chromosome, particularly at the first 'entry' sites of Xist. This study demonstrates that dosage-compensation failure has an effect as early as the blastocyst stage and reveals genetic and epigenetic contributions to orchestrating transcriptional silencing of the X chromosome during early embryogenesis.
This work was funded by a fellowship of Région Ile-de-France (DIM STEMP OLE) to M.B., the Paris Alliance of Cancer Research Institutes (PACRI-ANR) to LS and ERC Advanced Investigator award (ERC-2010-AdG–No.250367), EU FP7 grants SYBOSS (EU 7th Framework G.A. no. 242129) and MODHEP (EU 7th Framework G.A. no. 259743), La Ligue, Fondation de France, Labex DEEP (ANR-11-LBX-0044) part of the IDEX Idex PSL (ANR-10-IDEX-0001-02 PSL) and ABS4NGS (ANR-11-BINF-0001) to E.H and France Genomique National infrastructure (ANR-10-INBS09) to EH, NS, EB.
EC FP7 CP (242129)
External DOI: https://doi.org/10.1038/nsmb.3365
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263041