The initiation of imprinted X-chromosome inactivation absolutely requires Xist

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, PSL Research University scientists 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. They 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.

Paternal knockout of Xist impairs XCI,
dosage compensation and differentiation pathways

lncrna(a) Differences in ratios of X-chromosome expression levels to autosomal expression levels, from eight-cell to blastocyst stages in CB females (left) and XistpatΔ CB females (with a paternally inherited knockout allele) (right). (b) Heat map representing allele-specific mean expression from eight-cell to blastocyst stages of X-linked genes. (c) Major downregulated genes and pathways detected between CB WT and CB XistpatΔ females, as extracted from misregulated genes in the absence of paternal Xist. (d) Expression data of candidate genes from WT CB (black) and XistpatΔ CB (red) females, extracted from scRNA-seq data.

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.

Borensztein M, Syx L, Ancelin K, Diabangouaya P, Picard C, Liu T, Liang JB, Vassilev I, Galupa R, Servant N, Barillot E, Surani A, Chen CJ, Heard E. (2017) Xist-dependent imprinted X inactivation and the early developmental consequences of its failure. Nat Struct Mol Biol [Epub ahead of print]. [abstract]

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