This work was led by Ruta Meleckyte and Waz Varsally, with Ben Powell, Jasmin Zohren, and in collaboration with @astra-zeneca.bsky.social

You can also read a research briefing about the paper here: www.nature.com/articles/d41...

Thank you!

This project was a massive team effort, within our lab, with collaborators, and with help from @crick.ac.uk facilities @sermenchero.bsky.social @aureliencourtois.bsky.social and others not on Bluesky

In marsupials, X inactivation is imprinted, affecting the paternally-inherited X chromosome, and is thought to be regulated by the non-coding RNA RSX. When comparing sperm and oocytes at the RSX locus, we see a differentially methylated region, which might be a regulatory mechanism for imprinted XCI

Of course, we also dig into epigenetic regulation of X chromosome inactivation. The inactive X in adult marsupial cells adopts an unusual hypomethylated state – devoid of DNA methylation. Using our embryo data we show that the inactive X progressively loses methylation throughout early development

Our study suggests that a unique extra-embryonic methylation state is a conserved feature of mammals – and therefore is likely to be important for the evolution of the placenta

Secondly, after 5 days, DNA methylation drops, but does so largely in the extra-embryonic trophectoderm cells that will go to form the placenta, while remaining largely unchanged in the cells that give rise to the embryo proper

The paper provides two main important findings. Firstly, in contrast to mouse, early wiping of DNA methylation simply doesn’t happen in the marsupial embryos (up to day 5), with methylation levels remaining consistent during embryo genome activation and pluripotent stem cell formation

To address this question, we looked at the DNA methylation of marsupial embryos, which split from eutherian mammals 160 million years ago. By leveraging the more spaced out embryo development in marsupials we mapped changes in the epigenome to the processes described above

In eutherian (placental) mammals, the early embryo “wipes” its epigenome, but we don't know why. Many things happen early in placental mammalian embryos, and all in very quick succession: the embryo genome activates, pluripotent stem cells appear, and the placental precursor cells are formed

These well-defined cell lines provide a unique platform to investigate the role of sex as a biological variable across diverse cell types and to elucidate the impact of sex chromosome complement in human disease models 🧫🧬

Thanks, Lila!

Thank you, Maud!

This work was only possible because of the amazing facilities at @crick.ac.uk and our wonderful collaborators.

We generate a bulk and single nuclei RNAseq atlas of Y-gene KOs, identifying possible underlying molecular mechanisms causing spermatogenic defects. We see an interesting impact of Y genes on somatic cells of the testis

We make the equivalent of the human infertility AZFa deletion encompassing Uty, Ddx3y and Usp9y. We reveal phenotypes absent in single KOs, uncovering a detrimental cumulative effect of Y-gene loss on spermatogenesis.

The transcription activator Zfy2 promotes meiotic pairing and reciprocal recombination between the sex chromosomes.