Sex chromosomes shape the transcriptional landscape of the preimplantation mouse embryo

Background: Sex chromosomes are unique in how they are passed to the progeny – basically, there are two options:

• Mum (Xm) and dad (Xp) each pass on an X chromosome, but the Xp is inactivated (result: female embryo).
• Mum passes on an X chromosome (Xm), but dad a Y chromosome (result: male embryo).

In this preprint, the authors set out to resolve how mum and dad’s sex chromosomes sway the gene expression in mouse embryos before implantation.

Experimental Design:  This preprint combines two robust methods – genetic models (combinations of sex chromosomes) and scRNA-seq to uncover gene expression trends in developing mouse embryos.

Key findings:

• XX and XY embryos differ in gene expression – At the start of their study, the authors assessed if the male and female pre-implantation embryos differ in gene expression. Indeed, stark transcriptomic differences were evident at the 4-cell stage which progressively decreased with time. Interestingly, expression of genes in pathways related to metabolism differed between the two sexes.
• Autosomal gene expression is affected by sex chromosomes – The authors present two beautiful genetic experiments in support of the idea that sex chromosomes influence autosomal gene expression in trans.

1. Between XX and XY embryos, a large fraction of differentially expressed genes consisted of autosomal genes.
2. Embryos lacking an X chromosome (enigmatic OY embryos!) also showed changes in autosomal gene expression.

• Dosage of X or Y affects the trophectoderm: The most peculiar discovery presented in this preprint surfaces when the authors compare the transcriptomes of XmY or XmXp with XmO embryos. The transcriptome of the trophectoderm (which gives rise to placenta) was sensitive to the loss of either the Y chromosome or the inactive Xp chromosome.
• Parent of origin of the X chromosome influences pre-implantation development: It is not just the presence or dosage of the X chromosome that matters, but also the parental origin. Several well-thought-out experiments support this:

Embryos carrying only dad’s X (XpO)

1. developed slower, with fewer cells.
2. exhibited transcriptional delay.
3. had cells frequently falling in a confused cell-state cluster.
4. resulted in trophectoderm that was specified, but not maintained sufficiently.
5. showed the defects mentioned above independent of Xist-mediated imprinting.

In addition to all the above, the authors also identified a set of dad-X and mum-X biased genes that may influence the development of the embryo.

What I like about this preprint – The authors bring in a novel approach changing the way we look at gene regulation in pre-implantation embryo. The concept that sex chromosomes have an instructive role in autosomal gene expression and first cell-fate commitment opens delightful new avenues. If we were to see all the chromosomes as an army, the sex chromosomes (Xm, Xp, and Y) become commanders at the forefront.  In the discussion section of the preprint, the authors propose that in female embryos dad’s X chromosome encodes a repressor that silences dad’s X, which would be quite heroic too. The narrative running through this preprint reads like a treasure hunt in the black box of development , where every new finding makes one ponder what’s next.

Questions to the authors –

1. In the pre-implantation embryo, three developmental processes take the spotlight – the totipotency, first cell-fate (TE vs ICM), and second cell-fate (epiblast vs endoderm). Do you think sex chromosomes influence all these stages? If they do, do you envision a unifying mechanism?
2. How frequent is the occurrence of transposable elements on X chromosomes? Can you speculate about the mechanism by which the X chromosome influences autosomal gene expression in trans?
3. Between XX and XY embryos, the gene expression difference was highest at E2.0 but decreased later. What is so peculiar about the 4-cell stage?
4. Trophectoderm is sensitive to sex chromosomes. How can we interpret this finding from an evolutionary point of view?
5. Do you think sex chromosomes will have a similar or perhaps more profound effect on human pre-implantation development as well?

 

 

 

doi: https://doi.org/10.1242/prelights.39371

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