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Nat Struct Mol Biol. 2017 Mar;24(3):226-233. doi: 10.1038/nsmb.3365. Epub 2017 Jan 30.

Xist-dependent imprinted X inactivation and the early developmental consequences of its failure.

Author information

1
Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.
2
Institut Curie, PSL Research University, Mines Paris Tech, Bioinformatics and Computational Systems Biology of Cancer, INSERM U900, F-75005, Paris, France.
3
Annoroad Gene Technology Co., Ltd, Beijing, China.
4
Wellcome Trust Cancer Research UK Gurdon Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.

Abstract

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.

PMID:
28134930
PMCID:
PMC5337400
DOI:
10.1038/nsmb.3365
[Indexed for MEDLINE]
Free PMC Article

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