Xist-dependent imprinted X inactivation and the early developmental consequences of its failure
Nature Structural and Molecular Biology
Nature Publishing Group
MetadataShow full item record
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.
European Commission (242129)
External DOI: https://doi.org/10.1038/nsmb.3365
This record's URL: https://www.repository.cam.ac.uk/handle/1810/263041