Finally out! 🥳 Our paper showing how a transposable element (TE) insertion can cause developmental phenotypes is now published @natgenet.nature.com 🧬🦠🐁 Below is a brief description of the major findings. Check the full version of the paper for more details: www.nature.com/articles/s41588-025-02248-5
We used a model of TE-linked limb malformation in mice to gain insight into transposon biology during post-implantation development. A MusD element insertion upstream of the Fgf8 gene was reported to cause Dactylaplasia (Kano et al. 2009, Schwarzer & Aktas thesis dissertations) 1/
TE insertions can disrupt genes or act as enhancer/alternative promoters. Here, we show that the MusD insertion does NOT affect local gene expression. Instead, it is incorporated into the Fgf8 regulatory domain and adopts its enhancers, causing its co-expression with Fgf8 2/
Using confocal and electron microscopy, we showed that MusD expression in the same cells as Fgf8 leads to the production of intracellular viral-like particles (VLPs) in the embryo 🦠 3/
VLPs in the apical ectodermal ridge (AER) cells of the limb are toxic: we observed DNA damage and apoptotic cell death ☠️ at the time of digit outgrowth, causing the limb phenotype observed in adult mice 4/
But how do MusD VLPs in the cell drive this phenotype? 🤔 We generated 5 mutants of the MusD sequence. Our results showed that the Gag capsid is essential to drive a phenotype, but is not sufficient to generate the severe Dactylaplasia phenotype when reverse transcription is prevented. 5/
Overall, we describe how VLP production in post-implantation embryos can interfere with organ formation 6/
Our findings also provide a mechanism by which TE insertion uses the local regulatory landscape, restricted by 3D genome boundaries. We show insertion of the MusD in the neighboring but separated Lbx1 regulatory domain leads to expression in a different limb developmental population 7/
This work was done in @stemundi.bsky.social lab @molgen.mpg.de, funded by @hfspo.bsky.social . THANK YOU to all authors & the amazing colleagues I was very lucky to work with❤️ We also thank the reviewers for their supportive comments & helpful suggestions, which improved a lot our manuscript! 8/
Lastly, this work raises many new questions! Can VLPs cause other developmental pathologies? Why are certain developmental cells more vulnerable to VLPs than others? More generally, how do TE insertions contribute to pathological and healthy developmental phenotypes? 👇👇 9/
My newly established lab @mpi-ie.bsky.social will investigate these questions & everything related to TEs in mammalian development. Please get in touch if you are interested! 10/10
Fantastic Juliane! Congratulations 🥂
Very nice Juliane, great to see it out!
Phenomenal work! Congrats, Juliane and all authors 🎉
Very cool! Congratulations! :D
Congrats for publishing the peer-reviewed version of this outstanding work!
Congrats 🎉🎊 beautiful story 🤩
Thank you Olga!
Congratulations Juliane!
Nice work! It looks like the TE works like an enhancer trap recapitulating the regulatory input in a genomic regulatory block (GRB). A 2005 paper by Tom Becker "caught" a number of these blocks in zebrafish this way doi.org/10.1242/dev.... and we interpreted how they work in doi.org/10.1101/gr.6...
Thank you! Very interesting papers, thanks for sharing. I am curious what makes TE promoter responsive to any (?) reg. input (the viral origin?) & how common it is!! A recent paper from @ksiudeja.bsky.social lab show co-option of reg. sequences by an LTR in flies (academic.oup.com/nar/article/...)
As far as I know, MusD promoter is active in somatic cells as long as it is not (DNA) methylated or heterochromatinised (H3K9me3). Why does it respond like Fgf8 here? It might be a sensor of the entire enhancer landscape (which we know that the Fgf8 promoter is), or alternatively...
... notes that Fgf8 is kept silent by near-locus wide Polycomb binding, which spreads into your insertion region. It might be that Fgf8's Polycomb spreads across the MusD element, preventing DNA methylation and H3K9me3 deposition. So it is silent as long as Fgf8 is, and...
... when Fgf8 is activated, the whole locus loses Polycomb, and MusD finds itself derepressed. If this is true, that means that it is not the Fgf8 enhancers that control its promoter but just its Polycomb repression, which is in sync with that of Fgf8. This is all speculation, of course.
Thank you for your comments and thoughts! In the paper we tested whether the MusD will respond to enhancers at 3 other developmental loci and it does! So we don’t think it is related to Fgf8 landscape but rather the MusD promoter itself
Also, in Bl6 mice, the MusD is methylated and silenced despite being inserted at the same position (figure 1 and reported previously in Kano et al.)- this is caused by a polymorphism between mouse strains (what exactly is still under investigation 😉)
Quite possible - but the repression could still be Polycomb-mediated, especially since you notice that the MusD demethylation is constitutive there. And many developmental loci have Polycomb marks that spread widely from the target gene itself.
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Congrats Juliane!!! So cool to see the final version published 😁🤩
Beautiful work Juliane!!! So nice to see this final, fancy version 🤩
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Fantastic work congrats to all!!
Congrats!