Xist-dependent imprinted X inactivation and the early developmental consequences of its failure
M. Borensztein et al. (2017) Nature Structural & Molecular Biology DOI:10.1038/nsmb.3365
[Advance Online Publication Monday 30 January 2017]
Lead author Maud Borensztein explains: "In this paper, we describe the requirements and timing of X inactivation during pre-implantation embryogenesis, as well as the molecular events that occur when it fails, using single cell, allele-specific RNA sequencing of embryos derived from mice with polymorphic X chromosomes.
Our single cell in vivo data reveals that in Xist-mutant embryos, there are major perturbation of both extraembryonic development and pluripotency pathways, detected as early as the blastocyst stage, several days before the death of the embryo, following implantation.
We also uncover some unexpected actors involved this mis-regulation, including the imprinted, X-linked Rhox5 gene. This paper provides many novel insights into Xist lncRNA-mediated gene silencing and epigenetic events in a developmental context."
Abstract from the paper
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.
Read more about research in the Surani lab.
Hear Maud Borensztein answer listeners' questions, such as 'How much does a cell weigh?' in this Naked Scientists podcast.