Many thanks to Evans Bardot @ebardot.bsky.social and the editorial team for their thoughtful handling of this piece.

Thank you also to the funders @fwovlaanderen.bsky.social, @kuleuvenuniversity.bsky.social. @isdb.bsky.social, @isscr.org

Congratulations to co-first authors Sam van Knippenberg & Maria Tryfonos. Many thanks to collaborators Hilde Van de Velde, Joke De Busscher, Suresh Poovathingal, Marta Wojno, the Thierry Voet & Laurent DAVID lab, the patients who kindly donated embryos.

If you are interested: read the preprint here: www.biorxiv.org/content/10.64898/2025.12.01.691499v1

Our work underlines the importance of chromatin processes in early human development, provides a framework for understanding how 𝗰𝗵𝗿𝗼𝗺𝗮𝘁𝗶𝗻 𝗿𝗲𝗺𝗼𝗱𝗲𝗹𝗹𝗶𝗻𝗴 𝗰𝗼𝗻𝘁𝗿𝗶𝗯𝘂𝘁𝗲𝘀 𝘁𝗼 𝗰𝗲𝗹𝗹 𝗳𝗮𝘁𝗲 𝗮𝗰𝗾𝘂𝗶𝘀𝗶𝘁𝗶𝗼𝗻 𝗶𝗻 𝗲𝗺𝗯𝗿𝘆𝗼𝗴𝗲𝗻𝗲𝘀𝗶𝘀, and provides further insight into how stem cell embryo models recapitulate human development.

📈 𝗪𝗵𝘆 𝗧𝗵𝗶𝘀 𝗠𝗮𝘁𝘁𝗲𝗿𝘀
It is estimated that around 30% of human fertilisations fail to develop past the first week, and around 1 in 6 people worldwide struggle with infertility. It is therefore of paramount importance that we better understand the fundamental mechanisms underlying human development.

🔬 We found that:
• The SWI/SNF complex is necessary for 𝗶𝗻𝗻𝗲𝗿 𝗰𝗲𝗹𝗹 𝗺𝗮𝘀𝘀 𝗳𝗼𝗿𝗺𝗮𝘁𝗶𝗼𝗻 in human 𝗯𝗹𝗮𝘀𝘁𝗼𝗰𝘆𝘀𝘁𝘀. ✅
• The SWI/SNF complex safeguards 𝗲𝗽𝗶𝗯𝗹𝗮𝘀𝘁 formation in 𝗯𝗹𝗮𝘀𝘁𝗼𝗶𝗱𝘀. 🛡️
• The 𝘁𝗿𝗼𝗽𝗵𝗲𝗰𝘁𝗼𝗱𝗲𝗿𝗺 𝗴𝗲𝗻𝗲 𝗿𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗻𝗲𝘁𝘄𝗼𝗿𝗸 requires the SWI/SNF complex for 𝗰𝗶𝘀-𝗿𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗲𝗹𝗲𝗺𝗲𝗻𝘁𝘀 𝗮𝗰𝗰𝗲𝘀𝘀𝗶𝗯𝗶𝗹𝗶𝘁𝘆. 🧬

We depleted SWI/SNF-ATPases 𝗦𝗠𝗔𝗥𝗖𝗔𝟮 𝗮𝗻𝗱 𝗦𝗠𝗔𝗥𝗖𝗔𝟰 during 𝘁𝗿𝗼𝗽𝗵𝗲𝗰𝘁𝗼𝗱𝗲𝗿𝗺 𝗱𝗶𝗳𝗳𝗲𝗿𝗲𝗻𝘁𝗶𝗮𝘁𝗶𝗼𝗻, 𝗵𝘂𝗺𝗮𝗻 𝗯𝗹𝗮𝘀𝘁𝗼𝗶𝗱 𝗳𝗼𝗿𝗺𝗮𝘁𝗶𝗼𝗻, and 𝗵𝘂𝗺𝗮𝗻 𝗯𝗹𝗮𝘀𝘁𝗼𝗰𝘆𝘀𝘁 𝗱𝗲𝘃𝗲𝗹𝗼𝗽𝗺𝗲𝗻𝘁. We then performed 𝘀𝗶𝗻𝗴𝗹𝗲-𝗻𝘂𝗰𝗹𝗲𝗶 𝗺𝘂𝗹𝘁𝗶-𝗼𝗺𝗶𝗰 𝗴𝗲𝗻𝗲 𝗲𝘅𝗽𝗿𝗲𝘀𝘀𝗶𝗼𝗻 𝗮𝗻𝗱 𝗔𝗧𝗔𝗖 𝗽𝗿𝗼𝗳𝗶𝗹𝗶𝗻𝗴 of SWI/SNF-perturbed human blastoids.

In collaboration with Hilde Van de Velde's lab, we investigated the role of the 𝗦𝗪𝗜/𝗦𝗡𝗙 𝗰𝗵𝗿𝗼𝗺𝗮𝘁𝗶𝗻 𝗿𝗲𝗺𝗼𝗱𝗲𝗹𝗹𝗶𝗻𝗴 𝗰𝗼𝗺𝗽𝗹𝗲𝘅 in regulating cell identity during the first week of human development.

The formation of these cell lineages is driven by gene regulatory networks and coincides with major chromatin remodelling.

The first week of human development is a fascinating period, during which the human embryo develops from a single cell to a blastocyst containing both embryonic and extraembryonic cell lineages.

We are grateful for the support from the funders: @fwovlaanderen.bsky.social , @kuleuvenuniversity.bsky.social , @erc.europa.eu, @mrc-lms.bsky.social, @wellcometrust.bsky.social

This work was a collaborative effort.
A big thanks to all collaborators and funders, in particular: Claire Rougeulle @crougeulle.bsky.social, Jean-François Ouimette @jfouimette.bsky.social
Great contributions from Joost Gribnau, Kathy Niakan @niakanlab.bsky.social, Peter Rugg-Gunn, and others.

𝐓𝐡𝐞 𝐢𝐧𝐚𝐜𝐭𝐢𝐯𝐞 𝐗 𝐜𝐡𝐫𝐨𝐦𝐨𝐬𝐨𝐦𝐞 𝐡𝐚𝐬 𝐚𝐧 𝐮𝐧𝐮𝐬𝐮𝐚𝐥 𝐜𝐡𝐫𝐨𝐦𝐚𝐭𝐢𝐧 𝐬𝐭𝐚𝐭𝐮𝐬 𝐢𝐧 𝐡𝐮𝐦𝐚𝐧 𝐞𝐱𝐭𝐫𝐚𝐞𝐦𝐛𝐫𝐲𝐨𝐧𝐢𝐜 𝐜𝐞𝐥𝐥𝐬
Unlike mice, the inactive X chromosome of extraembryonic cells adopts an unusual chromatin landscape, revealing species-specific epigenetic events for the establishment of X inactivation in extraembryonic cells.

𝐗𝐈𝐒𝐓 𝐢𝐬 𝐫𝐞𝐪𝐮𝐢𝐫𝐞𝐝 𝐟𝐨𝐫 𝐭𝐡𝐞 𝐞𝐬𝐭𝐚𝐛𝐥𝐢𝐬𝐡𝐦𝐞𝐧𝐭 𝐨𝐟 𝐡𝐮𝐦𝐚𝐧 𝐗-𝐜𝐡𝐫𝐨𝐦𝐨𝐬𝐨𝐦𝐞 𝐢𝐧𝐚𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧.
Using the loss of function approach, we show that without XIST, extraembryonic cells fail to establish X-chromosome inactivation, providing the first formal proof that XIST is required for X-chromosome inactivation in humans.

The differentiation of naive pluripotent stem cells to two key postimplantation human extraembryonic cell types, extraembryonic mesoderm and trophoblast stem cells, triggers X-chromosome inactivation, robustly recapitulating human X-chromosome inactivation in human extraembryonic cells in vitro.

𝐊𝐞𝐲 𝐅𝐢𝐧𝐝𝐢𝐧𝐠𝐬: 𝐍𝐚𝐢𝐯𝐞 𝐡𝐮𝐦𝐚𝐧 𝐩𝐥𝐮𝐫𝐢𝐩𝐨𝐭𝐞𝐧𝐭 𝐬𝐭𝐞𝐦 𝐜𝐞𝐥𝐥𝐬 𝐭𝐨 𝐞𝐱𝐭𝐫𝐚𝐞𝐦𝐛𝐫𝐲𝐨𝐧𝐢𝐜 𝐜𝐞𝐥𝐥 𝐝𝐢𝐟𝐟𝐞𝐫𝐞𝐧𝐭𝐢𝐚𝐭𝐢𝐨𝐧 𝐢𝐧𝐝𝐮𝐜𝐞𝐬 𝐝𝐞 𝐧𝐨𝐯𝐨 𝐗-𝐜𝐡𝐫𝐨𝐦𝐨𝐬𝐨𝐦𝐞 𝐢𝐧𝐚𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧 𝐢𝐧 𝐡𝐮𝐦𝐚𝐧𝐬.

Yet,
Is XIST required to initiate X-chromosome inactivation in early human extraembryonic lineages?

Is X-chromosome inactivation required for female human embryo development?

𝐎𝐮𝐫 𝐧𝐞𝐰 𝐰𝐨𝐫𝐤 𝐭𝐚𝐤𝐞𝐬 𝐚 𝐦𝐚𝐣𝐨𝐫 𝐬𝐭𝐞𝐩 𝐭𝐨𝐰𝐚𝐫𝐝 𝐬𝐨𝐥𝐯𝐢𝐧𝐠 𝐭𝐡𝐢𝐬 𝐩𝐮𝐳𝐳𝐥𝐞.

𝐖𝐡𝐲 𝐝𝐨𝐞𝐬 𝐭𝐡𝐢𝐬 𝐦𝐚𝐭𝐭𝐞𝐫?
In mice, X-chromosome dosage compensation is absolutely essential for early female embryo development.

But humans are different!

Recent advances revealed that 𝐭𝐡𝐞 𝐭𝐢𝐦𝐢𝐧𝐠, 𝐝𝐲𝐧𝐚𝐦𝐢𝐜𝐬, 𝐚𝐧𝐝 𝐜𝐡𝐫𝐨𝐦𝐚𝐭𝐢𝐧 𝐟𝐞𝐚𝐭𝐮𝐫𝐞𝐬 𝐨𝐟 𝐗-𝐜𝐡𝐫𝐨𝐦𝐨𝐬𝐨𝐦𝐞 𝐢𝐧𝐚𝐜𝐭𝐢𝐯𝐚𝐭𝐢𝐨𝐧 𝐢𝐧 𝐡𝐮𝐦𝐚𝐧𝐬 𝐝𝐢𝐟𝐟𝐞𝐫 𝐩𝐫𝐨𝐟𝐨𝐮𝐧𝐝𝐥𝐲 𝐟𝐫𝐨𝐦 𝐦𝐢𝐜𝐞.